NM_000492.4(CFTR):c.1495C>T (p.Pro499Ser) AND Cystic fibrosis

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Sep 12, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001206975.11

Allele description [Variation Report for NM_000492.4(CFTR):c.1495C>T (p.Pro499Ser)]

NM_000492.4(CFTR):c.1495C>T (p.Pro499Ser)

Genes:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
CFTR-AS1:CFTR antisense RNA 1 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.1495C>T (p.Pro499Ser)

HGVS:

NC_000007.14:g.117559566C>T
NG_016465.4:g.98783C>T
NM_000492.4:c.1495C>TMANE SELECT
NP_000483.3:p.Pro499Ser
NP_000483.3:p.Pro499Ser
LRG_663t1:c.1495C>T
LRG_663:g.98783C>T
LRG_663p1:p.Pro499Ser
NC_000007.13:g.117199620C>T
NM_000492.3:c.1495C>T
NM_000492.4:c.1495C>T

Protein change:

P499S

Links:

dbSNP: rs397508219

NCBI 1000 Genomes Browser:

rs397508219

Molecular consequence:

NM_000492.4:c.1495C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

Recent activity

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cytochrome c oxidase subunit III (mitochondrion) [Motacilla tschutschensis taiva...
cytochrome c oxidase subunit III (mitochondrion) [Motacilla tschutschensis taivana]
gi|2214674064|ref|YP_010312854.1|

Protein
SAMN41088959 (1)
SRA
NADH dehydrogenase subunit 4 (mitochondrion) [Motacilla tschutschensis taivana]
NADH dehydrogenase subunit 4 (mitochondrion) [Motacilla tschutschensis taivana]
gi|2198160003|gb|ULM61912.1|

Protein
Plant sample from Hevea brasiliensis
Plant sample from Hevea brasiliensis

biosample
thymidine phosphorylase isoform 1 precursor [Homo sapiens]
thymidine phosphorylase isoform 1 precursor [Homo sapiens]
gi|166158925|ref|NP_001107228.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001378310	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 12, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32357917, 9630075, 28492532
SCV001460187	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV002027412	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002701288	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 10, 2020)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The true panel of cystic fibrosis mutations in the Sicilian population.

Chamayou S, Sicali M, Lombardo D, Maglia E, Liprino A, Cardea C, Fichera M, Venti E, Guglielmino A.

BMC Med Genet. 2020 May 1;21(1):89. doi: 10.1186/s12881-020-0958-9.

PubMed [citation]

PMID:: 32357917
PMCID:: PMC7195759

Congenital bilateral absence of vas deferens with a new missense mutation (P499A) in the CFTR gene.

Arduino C, Ferrone M, Brusco A, Garnerone S, Fontana D, Rolle L, Carbonara AO.

Clin Genet. 1998 Mar;53(3):202-4.

PubMed [citation]

PMID:: 9630075

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001378310.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 499 of the CFTR protein (p.Pro499Ser). 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 clinical features of CFTR-related conditions (PMID: 32357917). ClinVar contains an entry for this variant (Variation ID: 495898). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant disrupts the p.Pro499 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 9630075; Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001460187.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002027412.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002701288.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The p.P499S variant (also known as c.1495C>T), located in coding exon 11 of the CFTR gene, results from a C to T substitution at nucleotide position 1495. The proline at codon 499 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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