VCV000427059.29 - ClinVar

NM_000027.4(AGA):c.436T>G (p.Leu146Val)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(6); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000027.4(AGA):c.436T>G (p.Leu146Val)

Variation ID: 427059 Accession: VCV000427059.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q34.3 4: 177438816 (GRCh38) [ NCBI UCSC ] 4: 178359970 (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	May 22, 2017	Feb 14, 2024	Jan 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000027.4:c.436T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000018.2:p.Leu146Val	missense
NM_001171988.2:c.436T>G	NP_001165459.1:p.Leu146Val	missense
NR_033655.2:n.498T>G		non-coding transcript variant
NC_000004.12:g.177438816A>C
NC_000004.11:g.178359970A>C
NG_011845.2:g.8688T>G

... more HGVS ... less HGVS

Protein change

L146V

Other names

Canonical SPDI

NC_000004.12:177438815:A: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.

0.00140 (C)

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

Exome Aggregation Consortium (ExAC) 0.00094

The Genome Aggregation Database (gnomAD), exomes 0.00101

1000 Genomes Project 30x 0.00125

1000 Genomes Project 0.00140

The Genome Aggregation Database (gnomAD) 0.00188

Trans-Omics for Precision Medicine (TOPMed) 0.00234

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00277

Links

ClinGen: CA3146914 dbSNP: rs146381591 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.
AGA		-	-	GRCh38 GRCh37	532	627

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.
not provided	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Feb 6, 2020	RCV000489452.12
Aspartylglucosaminuria	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Jan 29, 2024	RCV000634564.26
Intellectual disability	Uncertain significance (1)	no assertion criteria provided	Jan 1, 2019	RCV001251883.3

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.
Uncertain significance (Sep 21, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aspartylglucosaminuria Affected status: unknown Allele origin: paternal	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000782733.1 First in ClinVar: May 28, 2018 Last updated: May 28, 2018
Uncertain significance (Aug 29, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000856364.1 First in ClinVar: May 22, 2017 Last updated: May 22, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=AGA Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Apr 27, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aspartylglucosaminuria Affected status: no Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000930199.1 First in ClinVar: Aug 04, 2019 Last updated: Aug 04, 2019	Geographic origin: Iran
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Aspartylglucosaminuria Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001306083.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Dec 16, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aspartylglucosaminuria Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429165.1 First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020	Number of individuals with the variant: 1
Uncertain significance (May 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aspartylglucosaminuria Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001623489.1 First in ClinVar: May 23, 2021 Last updated: May 23, 2021	Sex: mixed
Likely benign (Feb 06, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000577683.4 First in ClinVar: May 22, 2017 Last updated: May 22, 2017	Comment: 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: 30548430)
Likely benign (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Aspartylglucosaminuria Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000755894.7 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024
Uncertain significance (Jan 01, 2019)	no assertion criteria provided Method: clinical testing	Intellectual disability Affected status: yes Allele origin: unknown	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV001427629.1 First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020	Publications: PubMed (1) PubMed: 25741868
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798671.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001965469.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=AGA	-	-	-	-

Text-mined citations for rs146381591 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000027.4(AGA):c.436T>G (p.Leu146Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs146381591 ...