VCV000287080.46 - ClinVar

NM_000520.6(HEXA):c.1435G>A (p.Ala479Thr)

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.

(8)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000520.6(HEXA):c.1435G>A (p.Ala479Thr)

Variation ID: 287080 Accession: VCV000287080.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q23 15: 72345537 (GRCh38) [ NCBI UCSC ] 15: 72637878 (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	Dec 6, 2016	Oct 20, 2024	Jan 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000520.6:c.1435G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000511.2:p.Ala479Thr	missense
NM_000520.5:c.1435G>A
NM_001318825.2:c.1468G>A	NP_001305754.1:p.Ala490Thr	missense
NR_134869.3:n.1220G>A		non-coding transcript variant
NC_000015.10:g.72345537C>T
NC_000015.9:g.72637878C>T
NG_009017.2:g.35643G>A

... more HGVS ... less HGVS

Protein change

A479T, A490T

Other names

Canonical SPDI

NC_000015.10:72345536:C:T

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.

0.00280 (T)

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

The Genome Aggregation Database (gnomAD) 0.00038

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046

Trans-Omics for Precision Medicine (TOPMed) 0.00070

The Genome Aggregation Database (gnomAD), exomes 0.00089

Exome Aggregation Consortium (ExAC) 0.00090

1000 Genomes Project 30x 0.00234

1000 Genomes Project 0.00280

Links

ClinGen: CA7644676 dbSNP: rs145012038 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.
HEXA		-	-	GRCh38 GRCh37	1141	1175

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 specified	Benign (2)	criteria provided, multiple submitters, no conflicts	Jun 29, 2022	RCV000384004.7
Tay-Sachs disease	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Nov 3, 2022	RCV000505691.13
not provided	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jan 1, 2024	RCV000862163.29

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.
Likely benign (Aug 31, 2017)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Tay-Sachs disease (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000599896.1 First in ClinVar: Sep 26, 2017 Last updated: Sep 26, 2017	Sex: mixed
Benign (Apr 15, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000340739.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HEXA Number of individuals with the variant: 1 Sex: mixed
Likely benign (May 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Tay-Sachs disease Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001653477.1 First in ClinVar: Jun 03, 2021 Last updated: Jun 03, 2021	Sex: mixed
Benign (Apr 12, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001850209.1 First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021	Comment: This variant is associated with the following publications: (PMID: 31293106)
Benign (Jun 29, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000919504.2 First in ClinVar: Jun 02, 2019 Last updated: Aug 08, 2022	Publications: PubMed (1) PubMed: 31293106 Comment: Variant summary: HEXA c.1435G>A (p.Ala479Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain of the encoded protein … (more) Variant summary: HEXA c.1435G>A (p.Ala479Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain 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 0.00082 in 277154 control chromosomes, predominantly at a frequency of 0.0084 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in HEXA causing Tay-Sachs Disease phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1435G>A has been reported in the literature, without strong evidence for causality (Strom_2013). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified variant as VUS (n=1), likely benign (n=3), and benign (n=4). One of these labs also published an abstract in which they tested 4-5 patient samples for the variant of interest and found HexA enzyme analysis to show negative Tay-Sachs carrier state for all subjects (Counsyl abstract from Molecular Genetics and Metabolism, 2018). Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Nov 03, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Tay-Sachs disease Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001725342.4 First in ClinVar: Jun 15, 2021 Last updated: Apr 09, 2023
Likely benign (Jan 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001149514.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: HEXA: BS2 Number of individuals with the variant: 3
Likely benign (Mar 22, 2018)	no assertion criteria provided Method: clinical testing	Tay-Sachs disease Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002085662.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

Variant summary: HEXA c.1435G>A (p.Ala479Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain 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 0.00082 in 277154 control chromosomes, predominantly at a frequency of 0.0084 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in HEXA causing Tay-Sachs Disease phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1435G>A has been reported in the literature, without strong evidence for causality (Strom_2013). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified variant as VUS (n=1), likely benign (n=3), and benign (n=4). One of these labs also published an abstract in which they tested 4-5 patient samples for the variant of interest and found HexA enzyme analysis to show negative Tay-Sachs carrier state for all subjects (Counsyl abstract from Molecular Genetics and Metabolism, 2018). Based on the evidence outlined above, the variant was classified as benign.

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
Screening for Tay-Sachs disease carriers by full-exon sequencing with novel variant interpretation outperforms enzyme testing in a pan-ethnic cohort.	Cecchi AC	Molecular genetics & genomic medicine	2019	PMID: 31293106
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HEXA	-	-	-	-

Text-mined citations for rs145012038 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000520.6(HEXA):c.1435G>A (p.Ala479Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs145012038 ...