NM_000520.6(HEXA):c.1033G>A (p.Gly345Ser) AND Tay-Sachs disease

Clinical significance:Uncertain significance (Last evaluated: Jul 23, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000334575.3

Allele description [Variation Report for NM_000520.6(HEXA):c.1033G>A (p.Gly345Ser)]

NM_000520.6(HEXA):c.1033G>A (p.Gly345Ser)

Gene:
HEXA:hexosaminidase subunit alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q23
Genomic location:
Preferred name:
NM_000520.6(HEXA):c.1033G>A (p.Gly345Ser)
HGVS:
  • NC_000015.10:g.72348088C>T
  • NG_009017.1:g.33092G>A
  • NG_009017.2:g.33092G>A
  • NM_000520.6:c.1033G>AMANE SELECT
  • NM_000520.6:c.1033G>A
  • NM_001318825.2:c.1066G>A
  • NP_000511.2:p.Gly345Ser
  • NP_001305754.1:p.Gly356Ser
  • NC_000015.9:g.72640429C>T
  • NM_000520.4:c.1033G>A
  • NR_134869.2:n.1075G>A
Protein change:
G345S
Links:
dbSNP: rs775322979
NCBI 1000 Genomes Browser:
rs775322979
Molecular consequence:
  • NM_000520.6:c.1033G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001318825.2:c.1066G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_134869.2:n.1075G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Tay-Sachs disease (TSD)
Synonyms:
GM2 gangliosidosis, type 1; HexA deficiency; Hexosaminidase alpha-subunit deficiency (variant B); See all synonyms [MedGen]
Identifiers:
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)
OriginMethodCitations
SCV000393836Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Jun 14, 2016)
germlineclinical testing

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV000795436Counsylcriteria provided, single submitter
Uncertain significance
(Nov 16, 2017)
unknownclinical testing

Citation Link,

SCV001416526Invitaecriteria provided, single submitter
Uncertain significance
(Jul 23, 2019)
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
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes.

Coutelier M, Hammer MB, Stevanin G, Monin ML, Davoine CS, Mochel F, Labauge P, Ewenczyk C, Ding J, Gibbs JR, Hannequin D, Melki J, Toutain A, Laugel V, Forlani S, Charles P, Broussolle E, Thobois S, Afenjar A, Anheim M, Calvas P, Castelnovo G, et al.

JAMA Neurol. 2018 May 1;75(5):591-599. doi: 10.1001/jamaneurol.2017.5121.

PubMed [citation]
PMID:
29482223
PMCID:
PMC5885259

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]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000393836.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000795436.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001416526.1

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

Description

This sequence change replaces glycine with serine at codon 345 of the HEXA protein (p.Gly345Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs775322979, ExAC 0.002%). This variant has been observed in an individual with clinical features of ataxia (PMID: 29482223). ClinVar contains an entry for this variant (Variation ID: 317044). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 29, 2021

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