NM_000520.6(HEXA):c.805G>C (p.Gly269Arg) AND Tay-Sachs disease

Clinical significance:Likely pathogenic (Last evaluated: Aug 31, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000520.6(HEXA):c.805G>C (p.Gly269Arg)]

NM_000520.6(HEXA):c.805G>C (p.Gly269Arg)

HEXA:hexosaminidase subunit alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000520.6(HEXA):c.805G>C (p.Gly269Arg)
  • NC_000015.10:g.72350518C>G
  • NG_009017.1:g.30662G>C
  • NG_009017.2:g.30662G>C
  • NM_000520.6:c.805G>CMANE SELECT
  • NM_000520.6:c.805G>C
  • NM_001318825.2:c.838G>C
  • NP_000511.2:p.Gly269Arg
  • NP_001305754.1:p.Gly280Arg
  • NC_000015.9:g.72642859C>G
  • NM_000520.4:c.805G>C
  • NR_134869.2:n.847G>C
  • p.G269R
Protein change:
dbSNP: rs121907954
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000520.6:c.805G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318825.2:c.838G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_134869.2:n.847G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]


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)
SCV000494217Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Geneticsno assertion criteria providedPathogenic
(Dec 18, 2012)

PubMed (1)
[See all records that cite this PMID]

SCV001416055Invitaecriteria provided, single submitter
Likely pathogenic
(Aug 31, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
Indiangermlineyes1not providednot provided1not providedresearch



Expanding the spectrum of HEXA mutations in Indian patients with Tay-Sachs disease.

Sheth J, Mistri M, Datar C, Kalane U, Patil S, Kamate M, Shah H, Nampoothiri S, Gupta S, Sheth F.

Mol Genet Metab Rep. 2014;1:425-430.

PubMed [citation]

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
See all PubMed Citations (6)

Details of each submission

From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV000494217.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Indian1not providednot providedresearch PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1Bloodnot provided1not providednot providednot provided

From Invitae, SCV001416055.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)


This sequence change replaces glycine with arginine at codon 269 of the HEXA protein (p.Gly269Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 7 of the HEXA coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another HEXA variant in an individual affected with Tay–Sachs disease (PMID: 27896118). ClinVar contains an entry for this variant (Variation ID: 375357). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the c.805 nucleotide in the HEXA gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2522679, 20363167). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. 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: May 10, 2021

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