VCV000035821.54 - ClinVar

NM_000492.4(CFTR):c.1367T>C (p.Val456Ala)

Germline

Top reviewed classifications are shown here.

Submission summary:

27 submissions

24 submitters

9 conditions

Reviewed by expert panel

Pathogenic

Dec 2017 by CFTR2

for Cystic fibrosis

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.1367T>C (p.Val456Ala)

Variation ID: 35821 Accession: VCV000035821.54

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7q31.2 7: 117548798 (GRCh38) [ NCBI UCSC ] 7: 117188852 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 6, 2014	Oct 8, 2024	Dec 8, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.1367T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Val456Ala	missense
NC_000007.14:g.117548798T>C
NC_000007.13:g.117188852T>C
NG_016465.4:g.88015T>C
LRG_663:g.88015T>C
LRG_663t1:c.1367T>C	LRG_663p1:p.Val456Ala

... more HGVS ... less HGVS

Protein change

V456A

Other names

Canonical SPDI

NC_000007.14:117548797:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00060 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00020

Exome Aggregation Consortium (ExAC) 0.00024

1000 Genomes Project 30x 0.00047

1000 Genomes Project 0.00060

The Genome Aggregation Database (gnomAD) 0.00000

Links

ClinGen: CA325689 dbSNP: rs193922500 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CFTR		-	-	GRCh38 GRCh37	3825	5200
CFTR-AS1	-	-	-	GRCh38	-	512

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cystic fibrosis	Pathogenic (14)	reviewed by expert panel	Dec 8, 2017	RCV000029474.27
not provided	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jul 22, 2024	RCV000731635.23
Bronchiectasis with or without elevated sweat chloride 1 Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Hereditary pancreatitis	Pathogenic (1)	criteria provided, single submitter	May 13, 2022	RCV000763570.3
CFTR-related disorder Cystic fibrosis	Pathogenic (1)	criteria provided, single submitter	Mar 9, 2018	RCV001009542.1
not specified	Likely pathogenic (1)	criteria provided, single submitter	Mar 15, 2019	RCV001001125.8
Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis	Likely pathogenic (1)	criteria provided, single submitter	-	RCV001004447.1
Congenital bilateral aplasia of vas deferens from CFTR mutation	Pathogenic (1)	criteria provided, single submitter	Jun 26, 2019	RCV001331274.1
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (1)	criteria provided, single submitter	Mar 27, 2024	RCV003473123.2
CFTR-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 16, 2024	RCV004734530.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 08, 2017)	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013)) Method: research	Cystic fibrosis Affected status: yes Allele origin: germline	CFTR2 Accession: SCV000924258.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019	Other databases https://cftr2.org https://cftr2.org
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital bilateral aplasia of vas deferens from CFTR mutation Cystic fibrosis Affected status: unknown Allele origin: germline	Baylor Genetics Accession: SCV001163492.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020
Pathogenic (Nov 01, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052124.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 22, 2020	Publications: PubMed (13) PubMed: 14998948‚ 12544470‚ 17035430‚ 12357328‚ 16488363‚ 22423042‚ 25489051‚ 25735457‚ 26708955‚ 22395041‚ 26574590‚ 29805046‚ 31126253 Comment: Variant summary: CFTR c.1367T>C (p.Val456Ala) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains of the encoded protein … (more) Variant summary: CFTR c.1367T>C (p.Val456Ala) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 244518 control chromosomes (genomAD). This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0002 vs 0.013), allowing no conclusion about variant significance. c.1367T>C has been reported in the literature in multiple individuals (in compound heterozygous or homozygous states) affected with Cystic Fibrosis (Danziger_2004, McCormik_2002, Ziedalski_2006, Raraigh_2018, Indika_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing <10% of wild-type chloride conductance (Raraigh_2018). Six ClinVar submitters (evaluation after 2014) classified the variant as likely pathogenic (3x) and pathogenic (3x), including one expert panel (CFTR2) classified as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jun 26, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital bilateral aplasia of vas deferens from CFTR mutation Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001523279.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Likely pathogenic (Apr 13, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000486198.2 First in ClinVar: Feb 06, 2014 Last updated: Dec 24, 2022	Publications: PubMed (4) PubMed: 22423042‚ 17035430‚ 22395041‚ 12357328
Pathogenic (Dec 22, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000889282.4 First in ClinVar: Dec 16, 2018 Last updated: Jan 06, 2024	Publications: PubMed (20) PubMed: 12544470‚ 14998948‚ 17035430‚ 22423042‚ 26708955‚ 25651269‚ 26574590‚ 25735457‚ 28736296‚ 29216686‚ 30046002‚ 30348612‚ 31005549‚ 32906206‚ 22395041‚ 12357328‚ 25489051‚ 29805046‚ 31036917‚ 31126253 Comment: The frequency of this variant in the general population, 0.0016 (48/30028 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more) The frequency of this variant in the general population, 0.0016 (48/30028 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Cystic Fibrosis (CF) in a heterozygous state with another pathogenic variant (PMID: 12357328 (2002), 17035430 (2006), 22395041 (2012), 30348612 (2019)), and in a homozygous state (PMID: 22395041 (2012), 31126253 (2019)). It has also been reported in an asymptomatic individual in a homozygous state (PMID: 12544470 (2003)). Additionally, the variant was also reported in an individual with congenital bilateral absence of the vas deferens (CBAVD) (PMID: 14998948 (2004)). A functional study reported this variant resulted in only 4% of protein function compared to the wild type (PMID: 29805046 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Dec 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022516.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Nov 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848803.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The c.1367T>C (p.Val456Ala) variant in CFTR has been reported in the xompound heterozygous state with the CFTR p.Arg709X variant in at least 19 South Asian … (more) The c.1367T>C (p.Val456Ala) variant in CFTR has been reported in the xompound heterozygous state with the CFTR p.Arg709X variant in at least 19 South Asian individuals with cystic fibrosis and in the homozygous state in 2 South Asian individuals with cystic fibrosis (McCormick 2002 PMID: 12357328, Uppaluri 2012 PMID: 22395041, Indika 2019 PMID: 31126253). Both homozygous patients had mild to moderate phenotypes resulting in delayed diagnosis. It has also been identified in 0.25% (12/4804) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive allele frequency in the context of a prevalent disease. This variant has also been reported in ClinVar (Variation ID 35821). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein; however, in vivo functional studies in humans provide evidence that this variant impacts protein function (Masica 2015 PMID: 25489051, Raraigh 2018 PMID: 29805046). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PS3_Supporting. (less)
Likely pathogenic (Jan 23, 2024)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002701184.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 14998948‚ 17035430‚ 22395041‚ 22423042‚ 29805046 Comment: The p.V456A variant (also known as c.1367T>C), located in coding exon 10 of the CFTR gene, results from a T to C substitution at nucleotide … (more) The p.V456A variant (also known as c.1367T>C), located in coding exon 10 of the CFTR gene, results from a T to C substitution at nucleotide position 1367. The valine at codon 456 is replaced by alanine, an amino acid with similar properties. This variant was described in an individual with bronchiectasis and elevated sweat chloride in conjunction with p.F508del; however, the phase was not provided (Ziedalski TM et al. Chest, 2006 Oct;130:995-1002). This variant was also reported in two affected South Asian individuals; one homozygous individual had severe obstructive lung disease with Pseudomonas infection, pancreatic sufficiency, and an intermediate sweat chloride level while the second individual had this variant in conjunction with p.R709* and exhibited pancreatic sufficiency, mild lung disease, and intermediate sweat chloride levels (Uppaluri L et al. J. Cyst. Fibros., 2012 Jul;11:312-5). In addition, this variant was detected in one individual with congenital absence of the vas deferens (CBAVD), but a second CFTR alteration was not reported (Danziger KL et al. Hum. Reprod., 2004 Mar;19:540-6). Functional analysis of this variant in CFBE cells demonstrated 4% activity compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Pathogenic (Mar 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bronchiectasis with or without elevated sweat chloride 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004211618.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Sep 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	CFTR-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000916181.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (5) PubMed: 17035430‚ 14998948‚ 12357328‚ 22395041‚ 12544470 Comment: The CFTR c.1367T>C (p.Val456Ala) missense variant has been reported in five studies in which it is found in a total of nine individuals with CFTR-related … (more) The CFTR c.1367T>C (p.Val456Ala) missense variant has been reported in five studies in which it is found in a total of nine individuals with CFTR-related disorders, including in one in a homozygous state and in eight in a compound heterozygous state (McCormick et al. 2002; Strom et al. 2003; Danziger et al. 2004; Ziedalski et al. 2006; Uppaluri et al. 2012). Three of the compound heterozygotes carried the common p.Phe508del variant on the second allele and four carried the same stop-gained variant on the second allele. One of the compound heterozygotes who presented with only congenital bilateral absence of the vas deferens was compound heterozygous for the p.Val456Ala variant and a 5T allele (a variable repeat located in intron 8 of the CFTR gene considered to be a variably penetrant mutation and to decrease the efficiency of intron 8 splicing) (Danziger et al. 2004). Additionally, Strom et al. (2003) identified the p.Val456Ala variant in a homozygous state in an asymptomatic proband suggesting that this is a mild allele. Control data are unavailable for this variant, which is reported at a frequency of 0.00306 in the South Asian population of the 1000 Genomes Project. The reported cases suggest the variant is more likely to lead to a classic cystic fibrosis phenotype when inherited in compound heterozygous state with a severe allele. Based on the evidence from the literature, the p.Val456Ala variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Likely pathogenic (Mar 15, 2019)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001158265.1 First in ClinVar: Feb 10, 2020 Last updated: Feb 10, 2020	Comment: The CFTR c.1367T>C; p.Val456Ala variant (rs193922500) is reported as a CF-causing variant in the CFTR2 database, and CF patients with this variant are likely to … (more) The CFTR c.1367T>C; p.Val456Ala variant (rs193922500) is reported as a CF-causing variant in the CFTR2 database, and CF patients with this variant are likely to be pancreatic sufficient (see CFTR2 database link). This variant is reported in the literature in both the homozygous and compound heterozygous states in CF patients (McCormick 2002, Uppaluri 2012); however, one report of an asymptomatic patient who is homozygous for this variant, suggests that it may be a mild CF variant (Strom 2003). Functional analysis of the variant protein shows approximately 4% of wildtype protein activity (Raraigh 2018). This variant is reported as likely pathogenic in ClinVar (Variation ID: 35821). It is found in the South Asian general population with an allele frequency of 0.16% (48/30028 alleles) in the Genome Aggregation Database. The valine at codon 456 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. Based on available information, this variant is considered to be likely pathogenic. REFERENCES CFTR2 database: https://cftr2.org/ McCormick J et al. Demographics of the UK cystic fibrosis population: implications for neonatal screening. Eur J Hum Genet. 2002 Oct;10(10):583-90. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Strom CM et al. Extensive sequencing of the cystic fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a comprehensive test. Genet Med. 2003 Jan-Feb;5(1):9-14. Uppaluri L et al. Clinical evidence that V456A is a Cystic Fibrosis causing mutation in South Asians. J Cyst Fibros. 2012 Jul;11(4):312-5. (less)
Pathogenic (Mar 09, 2018)	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017)) Method: curation	cystic fibrosis CFTR-related disorders Affected status: yes Allele origin: germline	CFTR-France Accession: SCV001169637.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Publications: PubMed (1) PubMed: 28603918 Comment: the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
Pathogenic (Jan 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001478426.1 First in ClinVar: Feb 07, 2021 Last updated: Feb 07, 2021	Publications: PubMed (2) PubMed: 12544470‚ 22395041
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: yes Allele origin: germline	3billion Accession: SCV002318684.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (7) PubMed: 31005549‚ 22395041‚ 12357328‚ 29805046‚ 7505767‚ 30348612‚ 31126253 Comment: Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000035821, PMID:12357328). … (more) Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000035821, PMID:12357328). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 29805046). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:7505767). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.916>=0.6, 3CNET: 0.905>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0002079). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 31126253, 30348612, 31005549, 22395041). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Bronchiectasis (present)
Pathogenic (Sep 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Cystic fibrosis Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002573848.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Comment: This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project … (more) This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM2_SUP, PM3_STR, PM5, PP3, PP4 (less) Number of individuals with the variant: 1
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003853259.1 First in ClinVar: Apr 09, 2023 Last updated: Apr 09, 2023	Publications: PubMed (1) PubMed: 31126253 Comment: A Heterozygous Missense variant c.1367T>C in Exon 10 of the CFTR gene that results in the amino acid substitution p.Val456Ala was identified. The observed variant … (more) A Heterozygous Missense variant c.1367T>C in Exon 10 of the CFTR gene that results in the amino acid substitution p.Val456Ala was identified. The observed variant has a minor allele frequency of 0.00020/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 35821). This variant has been identified in patients affected with Cystic Fibrosis (Indika NLR et al., 2019). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. (less) Ethnicity/Population group: Asian Geographic origin: India
Likely pathogenic (Jan 31, 2018)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000859479.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR Number of individuals with the variant: 2 Sex: mixed
Likely pathogenic (May 10, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450060.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1
Pathogenic (Apr 30, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis Affected status: no Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059220.1 First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022
Pathogenic (May 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary pancreatitis Bronchiectasis with or without elevated sweat chloride 1 Cystic fibrosis Congenital bilateral aplasia of vas deferens from CFTR mutation Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894409.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Likely pathogenic (Aug 13, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714234.2 First in ClinVar: Jun 15, 2021 Last updated: Apr 09, 2023	Publications: PubMed (8) PubMed: 22395041‚ 12357328‚ 25489051‚ 17035430‚ 22423042‚ 28736296‚ 29805046‚ 29216686 Comment: PS3, PM2, PP3, PP5
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cystic fibrosis (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004101468.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023	Comment: The missense variant p.V456A in CFTR (NM_000492.3) has previously been reported in homozygous and compound heterozygous state (Ziedalski et al. 2006;Uppaluri et al. 2012). Experimental … (more) The missense variant p.V456A in CFTR (NM_000492.3) has previously been reported in homozygous and compound heterozygous state (Ziedalski et al. 2006;Uppaluri et al. 2012). Experimental studies reveal that the variant affects CFTR protein function (Raraigh et al 2018). The variant has been classified as Pathogenic in the ClinVar database. The p.V456A variant has a gnomAD exomes frequency of 0.02045 %. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Val456Ala in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of the respiratory system (present)
Pathogenic (Jan 28, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001574402.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 14998948‚ 17035430‚ 22395041‚ 22423042‚ 25489051‚ 12544470‚ 29805046‚ 30046002 Comment: This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 456 of the CFTR protein (p.Val456Ala). … (more) This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 456 of the CFTR protein (p.Val456Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with cystic fibrosis and congenital absence of the vas deferens (PMID: 14998948, 17035430, 22395041, 22423042, 25489051; Invitae). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (PMID: 12544470). ClinVar contains an entry for this variant (Variation ID: 35821). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 22, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001758624.5 First in ClinVar: Jul 24, 2021 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate this variant to impact function similar to other known CF-causing variants (PMID: 29805046); In silico analysis supports that this missense variant … (more) Published functional studies demonstrate this variant to impact function similar to other known CF-causing variants (PMID: 29805046); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29805046, 29216686, 25489051, 28502372, 22395041, 31126253, 31005549, 14998948, 12544470, 24149827, 12357328, 31036917, 34842611, 32366966, 32734384, 22423042, 35652053, 35857025, Conti 2023[Review], 35761057, 34782259, 37313453, 17035430, 38515211) (less)
Pathogenic (Jan 23, 2022)	no assertion criteria provided Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV002583259.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022	Publications: PubMed (4) PubMed: 12357328‚ 25489051‚ 29805046‚ 22395041
Pathogenic (Jul 16, 2024)	no assertion criteria provided Method: clinical testing	CFTR-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362512.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The CFTR c.1367T>C variant is predicted to result in the amino acid substitution p.Val456Ala. This variant has been reported in the compound heterozygous and homozygous … (more) The CFTR c.1367T>C variant is predicted to result in the amino acid substitution p.Val456Ala. This variant has been reported in the compound heterozygous and homozygous state in several patients with cystic fibrosis (McCormick et al. 2002. PubMed ID: 12357328; Uppaluri et al. 2012. PubMed ID: 22395041; Masica et al. 2015. PubMed ID: 25489051). In vitro functional studies showed that this variant resulted in significantly decreased function of CFTR (~4.1% of control) (Raraigh et al. 2018. PubMed ID: 29805046). This variant is reported in 0.16% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Comment:

Variant summary: CFTR c.1367T>C (p.Val456Ala) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 244518 control chromosomes (genomAD). This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0002 vs 0.013), allowing no conclusion about variant significance. c.1367T>C has been reported in the literature in multiple individuals (in compound heterozygous or homozygous states) affected with Cystic Fibrosis (Danziger_2004, McCormik_2002, Ziedalski_2006, Raraigh_2018, Indika_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing <10% of wild-type chloride conductance (Raraigh_2018). Six ClinVar submitters (evaluation after 2014) classified the variant as likely pathogenic (3x) and pathogenic (3x), including one expert panel (CFTR2) classified as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The frequency of this variant in the general population, 0.0016 (48/30028 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Cystic Fibrosis (CF) in a heterozygous state with another pathogenic variant (PMID: 12357328 (2002), 17035430 (2006), 22395041 (2012), 30348612 (2019)), and in a homozygous state (PMID: 22395041 (2012), 31126253 (2019)). It has also been reported in an asymptomatic individual in a homozygous state (PMID: 12544470 (2003)). Additionally, the variant was also reported in an individual with congenital bilateral absence of the vas deferens (CBAVD) (PMID: 14998948 (2004)). A functional study reported this variant resulted in only 4% of protein function compared to the wild type (PMID: 29805046 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

Comment:

The c.1367T>C (p.Val456Ala) variant in CFTR has been reported in the xompound heterozygous state with the CFTR p.Arg709X variant in at least 19 South Asian individuals with cystic fibrosis and in the homozygous state in 2 South Asian individuals with cystic fibrosis (McCormick 2002 PMID: 12357328, Uppaluri 2012 PMID: 22395041, Indika 2019 PMID: 31126253). Both homozygous patients had mild to moderate phenotypes resulting in delayed diagnosis. It has also been identified in 0.25% (12/4804) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with a recessive allele frequency in the context of a prevalent disease. This variant has also been reported in ClinVar (Variation ID 35821). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein; however, in vivo functional studies in humans provide evidence that this variant impacts protein function (Masica 2015 PMID: 25489051, Raraigh 2018 PMID: 29805046). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PS3_Supporting.

Comment:

The p.V456A variant (also known as c.1367T>C), located in coding exon 10 of the CFTR gene, results from a T to C substitution at nucleotide position 1367. The valine at codon 456 is replaced by alanine, an amino acid with similar properties. This variant was described in an individual with bronchiectasis and elevated sweat chloride in conjunction with p.F508del; however, the phase was not provided (Ziedalski TM et al. Chest, 2006 Oct;130:995-1002). This variant was also reported in two affected South Asian individuals; one homozygous individual had severe obstructive lung disease with Pseudomonas infection, pancreatic sufficiency, and an intermediate sweat chloride level while the second individual had this variant in conjunction with p.R709* and exhibited pancreatic sufficiency, mild lung disease, and intermediate sweat chloride levels (Uppaluri L et al. J. Cyst. Fibros., 2012 Jul;11:312-5). In addition, this variant was detected in one individual with congenital absence of the vas deferens (CBAVD), but a second CFTR alteration was not reported (Danziger KL et al. Hum. Reprod., 2004 Mar;19:540-6). Functional analysis of this variant in CFBE cells demonstrated 4% activity compared to wild type (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

The CFTR c.1367T>C (p.Val456Ala) missense variant has been reported in five studies in which it is found in a total of nine individuals with CFTR-related disorders, including in one in a homozygous state and in eight in a compound heterozygous state (McCormick et al. 2002; Strom et al. 2003; Danziger et al. 2004; Ziedalski et al. 2006; Uppaluri et al. 2012). Three of the compound heterozygotes carried the common p.Phe508del variant on the second allele and four carried the same stop-gained variant on the second allele. One of the compound heterozygotes who presented with only congenital bilateral absence of the vas deferens was compound heterozygous for the p.Val456Ala variant and a 5T allele (a variable repeat located in intron 8 of the CFTR gene considered to be a variably penetrant mutation and to decrease the efficiency of intron 8 splicing) (Danziger et al. 2004). Additionally, Strom et al. (2003) identified the p.Val456Ala variant in a homozygous state in an asymptomatic proband suggesting that this is a mild allele. Control data are unavailable for this variant, which is reported at a frequency of 0.00306 in the South Asian population of the 1000 Genomes Project. The reported cases suggest the variant is more likely to lead to a classic cystic fibrosis phenotype when inherited in compound heterozygous state with a severe allele. Based on the evidence from the literature, the p.Val456Ala variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

The CFTR c.1367T>C; p.Val456Ala variant (rs193922500) is reported as a CF-causing variant in the CFTR2 database, and CF patients with this variant are likely to be pancreatic sufficient (see CFTR2 database link). This variant is reported in the literature in both the homozygous and compound heterozygous states in CF patients (McCormick 2002, Uppaluri 2012); however, one report of an asymptomatic patient who is homozygous for this variant, suggests that it may be a mild CF variant (Strom 2003). Functional analysis of the variant protein shows approximately 4% of wildtype protein activity (Raraigh 2018). This variant is reported as likely pathogenic in ClinVar (Variation ID: 35821). It is found in the South Asian general population with an allele frequency of 0.16% (48/30028 alleles) in the Genome Aggregation Database. The valine at codon 456 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant may be deleterious. Based on available information, this variant is considered to be likely pathogenic. REFERENCES CFTR2 database: https://cftr2.org/ McCormick J et al. Demographics of the UK cystic fibrosis population: implications for neonatal screening. Eur J Hum Genet. 2002 Oct;10(10):583-90. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Strom CM et al. Extensive sequencing of the cystic fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a comprehensive test. Genet Med. 2003 Jan-Feb;5(1):9-14. Uppaluri L et al. Clinical evidence that V456A is a Cystic Fibrosis causing mutation in South Asians. J Cyst Fibros. 2012 Jul;11(4):312-5.

Comment:

Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000035821, PMID:12357328). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 29805046). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:7505767). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.916>=0.6, 3CNET: 0.905>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0002079). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 31126253, 30348612, 31005549, 22395041). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM2_SUP, PM3_STR, PM5, PP3, PP4

Comment:

A Heterozygous Missense variant c.1367T>C in Exon 10 of the CFTR gene that results in the amino acid substitution p.Val456Ala was identified. The observed variant has a minor allele frequency of 0.00020/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 35821). This variant has been identified in patients affected with Cystic Fibrosis (Indika NLR et al., 2019). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.

Comment:

The missense variant p.V456A in CFTR (NM_000492.3) has previously been reported in homozygous and compound heterozygous state (Ziedalski et al. 2006;Uppaluri et al. 2012). Experimental studies reveal that the variant affects CFTR protein function (Raraigh et al 2018). The variant has been classified as Pathogenic in the ClinVar database. The p.V456A variant has a gnomAD exomes frequency of 0.02045 %. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Val456Ala in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 456 of the CFTR protein (p.Val456Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with cystic fibrosis and congenital absence of the vas deferens (PMID: 14998948, 17035430, 22395041, 22423042, 25489051; Invitae). This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (PMID: 12544470). ClinVar contains an entry for this variant (Variation ID: 35821). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046, 30046002). For these reasons, this variant has been classified as Pathogenic.

Comment:

Published functional studies demonstrate this variant to impact function similar to other known CF-causing variants (PMID: 29805046); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29805046, 29216686, 25489051, 28502372, 22395041, 31126253, 31005549, 14998948, 12544470, 24149827, 12357328, 31036917, 34842611, 32366966, 32734384, 22423042, 35652053, 35857025, Conti 2023[Review], 35761057, 34782259, 37313453, 17035430, 38515211)

Comment:

The CFTR c.1367T>C variant is predicted to result in the amino acid substitution p.Val456Ala. This variant has been reported in the compound heterozygous and homozygous state in several patients with cystic fibrosis (McCormick et al. 2002. PubMed ID: 12357328; Uppaluri et al. 2012. PubMed ID: 22395041; Masica et al. 2015. PubMed ID: 25489051). In vitro functional studies showed that this variant resulted in significantly decreased function of CFTR (~4.1% of control) (Raraigh et al. 2018. PubMed ID: 29805046). This variant is reported in 0.16% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Frequency spectrum of rare and clinically relevant markers in multiethnic Indian populations (ClinIndb): A resource for genomic medicine in India.	Narang A	Human mutation	2020	PMID: 32906206
Phenotypic spectrum and genetic heterogeneity of cystic fibrosis in Sri Lanka.	Indika NLR	BMC medical genetics	2019	PMID: 31126253
Sequencing as a first-line methodology for cystic fibrosis carrier screening.	Beauchamp KA	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 31036917
Cystic fibrosis screen positive inconclusive diagnosis (CFSPID): Experience in Tuscany, Italy.	Terlizzi V	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2019	PMID: 31005549
Positive clinical response to ivacaftor treatment in an individual with the CFTR genotype F508del/V456A.	Bratcher PE	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2019	PMID: 30348612
Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators.	Han ST	JCI insight	2018	PMID: 30046002
Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity.	Raraigh KS	American journal of human genetics	2018	PMID: 29805046
Congenital bilateral absence of the vas deferens as an atypical form of cystic fibrosis: reproductive implications and genetic counseling.	de Souza DAS	Andrology	2018	PMID: 29216686
A New Targeted CFTR Mutation Panel Based on Next-Generation Sequencing Technology.	Lucarelli M	The Journal of molecular diagnostics : JMD	2017	PMID: 28736296
The Spectrum of CFTR Variants in Nonwhite Cystic Fibrosis Patients: Implications for Molecular Diagnostic Testing.	Schrijver I	The Journal of molecular diagnostics : JMD	2016	PMID: 26708955
Comparative ex vivo, in vitro and in silico analyses of a CFTR splicing mutation: Importance of functional studies to establish disease liability of mutations.	Ramalho AS	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2016	PMID: 25735457
Newborn Screening for Cystic Fibrosis in California.	Kharrazi M	Pediatrics	2015	PMID: 26574590
Elevated sweat chloride levels due to arsenic toxicity.	Mazumdar M	The New England journal of medicine	2015	PMID: 25651269
Missense variants in CFTR nucleotide-binding domains predict quantitative phenotypes associated with cystic fibrosis disease severity.	Masica DL	Human molecular genetics	2015	PMID: 25489051
Role of cystic fibrosis transmembrane conductance regulator in patients with chronic sinopulmonary disease.	Gonska T	Chest	2012	PMID: 22423042
Clinical evidence that V456A is a Cystic Fibrosis causing mutation in South Asians.	Uppaluri L	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2012	PMID: 22395041
Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection.	Ziedalski TM	Chest	2006	PMID: 17035430
Delayed diagnosis of females with respiratory presentation of cystic fibrosis did not segregate with poorer clinical outcome.	McCormick J	Journal of clinical epidemiology	2006	PMID: 16488363
Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis.	Danziger KL	Human reproduction (Oxford, England)	2004	PMID: 14998948
Extensive sequencing of the cystic fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a comprehensive test.	Strom CM	Genetics in medicine : official journal of the American College of Medical Genetics	2003	PMID: 12544470
Demographics of the UK cystic fibrosis population: implications for neonatal screening.	McCormick J	European journal of human genetics : EJHG	2002	PMID: 12357328
Exon 9 of the CFTR gene: splice site haplotypes and cystic fibrosis mutations.	Dörk T	Human genetics	1994	PMID: 7505767
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CFTR	-	-	-	-
https://cftr2.org	-	-	-	-
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Text-mined citations for rs193922500 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.1367T>C (p.Val456Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs193922500 ...