NM_000520.6(HEXA):c.1171G>A (p.Val391Met) AND Tay-Sachs disease

Clinical significance:Likely pathogenic (Last evaluated: Sep 2, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000520.6(HEXA):c.1171G>A (p.Val391Met)]

NM_000520.6(HEXA):c.1171G>A (p.Val391Met)

HEXA:hexosaminidase subunit alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000520.6(HEXA):c.1171G>A (p.Val391Met)
  • NC_000015.10:g.72346686C>T
  • NG_009017.2:g.34494G>A
  • NM_000520.6:c.1171G>AMANE SELECT
  • NM_001318825.2:c.1204G>A
  • NP_000511.2:p.Val391Met
  • NP_001305754.1:p.Val402Met
  • NC_000015.9:g.72639027C>T
Protein change:
Molecular consequence:
  • NM_000520.6:c.1171G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318825.2:c.1204G>A - missense variant - [Sequence Ontology: SO:0001583]


Tay-Sachs disease (TSD)
GM2 gangliosidosis, type 1; HexA deficiency; Hexosaminidase alpha-subunit deficiency (variant B); See all synonyms [MedGen]
MONDO: MONDO:0010100; MedGen: C0039373; Orphanet: 845; OMIM: 272800

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001576692Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 2, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing



A new mutation in the HEXA gene associated with a spinal muscular atrophy phenotype.

Navon R, Khosravi R, Korczyn T, Masson M, Sonnino S, Fardeau M, Eymard B, Lefevre M, Turpin JC, Rondot P, et al.

Neurology. 1995 Mar;45(3 Pt 1):539-43.

PubMed [citation]

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

Details of each submission

From Invitae, SCV001576692.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)


This sequence change replaces valine with methionine at codon 391 of the HEXA protein (p.Val391Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Tay-Sachs disease (PMID: 7898712). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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