VCV000375365.14 - ClinVar

NM_000520.6(HEXA):c.1454G>A (p.Trp485Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (1); Likely pathogenic (1)

2 out of 4 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000520.6(HEXA):c.1454G>A (p.Trp485Ter)

Variation ID: 375365 Accession: VCV000375365.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q23 15: 72345518 (GRCh38) [ NCBI UCSC ] 15: 72637859 (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 4, 2017	Mar 28, 2026	Mar 7, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000520.6:c.1454G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000511.2:p.Trp485Ter	nonsense
NM_001318825.2:c.1487G>A	NP_001305754.1:p.Trp496Ter	nonsense
NR_134869.3:n.1239G>A		non-coding transcript variant
NC_000015.10:g.72345518C>T
NC_000015.9:g.72637859C>T
NG_009017.2:g.35662G>A

... more HGVS ... less HGVS

Protein change

W485*, W496*

Other names

Canonical SPDI

NC_000015.10:72345517:C:T

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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA16044196 dbSNP: rs1057519468 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	1359	1390

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.
Tay-Sachs disease	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 7, 2026	RCV000416424.15

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.	Expand all rows Collapse all rows 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 pathogenic (Mar 07, 2026) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Tay-Sachs disease (Autosomal recessive inheritance)	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV007518000.1 First in ClinVar: Mar 28, 2026 Last updated: Mar 28, 2026	Publications: pmc: PMC3897787 pmc: PMC3897787 Comment: show A known stopgain variant, c.1454G>A in exon 13 of HEXA was observed in heterozygous state in the proband (Sheth et al., 2013; ClinVar ID: VCV000375365.13). Sanger validation and segregation showed that the variant was present in a heterozygous state in her and her husband. This variant is present in one individual in heterozygous state and absent in homozygous state in the population database gnomAD (v.4.1.0). This variant is absent in homozygous and/or heterozygous state in our in-house database of 4037 exomes. This variant is predicted to introduce a premature termination codon which may either trigger nonsense-mediated mRNA decay or result in a truncated protein product. The clinical findings observed in their previous child are in concordance with Tay-Sachs disease. (less) Observation: 1 Collection method: research Allele origin: unknown Affected status: yes more Observation 1 Collection method: research Allele origin: unknown Affected status: yes Sex: female

Pathogenic (Feb 24, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Tay-Sachs disease	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000815194.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 1833974‚ 23852624‚ 28492532‚ 8490625 Comment: show This sequence change creates a premature translational stop signal (p.Trp485*) in the HEXA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Tay-Sachs disease (PMID: 23852624). ClinVar contains an entry for this variant (Variation ID: 375365). Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 24, 2012) N Not contributing to aggregate classification	no assertion criteria provided	Tay-Sachs disease (Autosomal recessive inheritance)	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV000494228.2 First in ClinVar: Feb 04, 2017 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 23852624 Observation: 1 Collection method: research Allele origin: germline Affected status: yes more Observation 1 Collection method: research Allele origin: germline Affected status: yes Clinical Features: Developmental regression (present) , Cherry red spot of the macula (present) , Muscular hypotonia (present) , Seizures (present) , Hearing impairment (present) Zygosity: 1 Homozygote Age: 0-9 years Sex: male Ethnicity/Population group: Indian Geographic origin: India Tissue: Blood Method: Polymerase Chain Reaction followed by bi-directional Sanger sequencing was performed covering all exons and exon-intron boundaries of the HEXA gene.

Pathogenic (Aug 17, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Tay-Sachs disease	Natera, Inc. Accession: SCV002085660.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

A known stopgain variant, c.1454G>A in exon 13 of HEXA was observed in heterozygous state in the proband (Sheth et al., 2013; ClinVar ID: VCV000375365.13). Sanger validation and segregation showed that the variant was present in a heterozygous state in her and her husband. This variant is present in one individual in heterozygous state and absent in homozygous state in the population database gnomAD (v.4.1.0). This variant is absent in homozygous and/or heterozygous state in our in-house database of 4037 exomes. This variant is predicted to introduce a premature termination codon which may either trigger nonsense-mediated mRNA decay or result in a truncated protein product. The clinical findings observed in their previous child are in concordance with Tay-Sachs disease.

Comment:

This sequence change creates a premature translational stop signal (p.Trp485*) in the HEXA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Tay-Sachs disease (PMID: 23852624). ClinVar contains an entry for this variant (Variation ID: 375365). Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Burden of lysosomal storage disorders in India: experience of 387 affected children from a single diagnostic facility.	Sheth J	JIMD reports	2014	PMID: 23852624
Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.	Akli S	Human molecular genetics	1993	PMID: 8490625
Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.	Triggs-Raine BL	American journal of human genetics	1991	PMID: 1833974
-	-	-	-	PMC3897787

Text-mined citations for rs1057519468 ...

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 Apr 13, 2026