NM_000520.6(HEXA):c.929_930del (p.Ser310fs) AND Tay-Sachs disease

Clinical significance:Pathogenic (Last evaluated: Feb 6, 2020)

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:
RCV000681660.3

Allele description [Variation Report for NM_000520.6(HEXA):c.929_930del (p.Ser310fs)]

NM_000520.6(HEXA):c.929_930del (p.Ser310fs)

Gene:
HEXA:hexosaminidase subunit alpha [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
15q23
Genomic location:
Preferred name:
NM_000520.6(HEXA):c.929_930del (p.Ser310fs)
HGVS:
  • NC_000015.10:g.72349135AG[1]
  • NG_009017.2:g.32042CT[1]
  • NM_000520.6:c.929_930delMANE SELECT
  • NM_000520.6:c.929_930del
  • NM_001318825.2:c.962_963del
  • NP_000511.2:p.Ser310fs
  • NP_001305754.1:p.Ser321fs
  • NC_000015.9:g.72641476AG[1]
  • NC_000015.9:g.72641476_72641477del
  • NM_000520.4:c.929_930del
  • NM_000520.4:c.929_930delCT
  • NM_000520.5:c.929_930del
  • NR_134869.3:n.969CT[1]
Protein change:
S310fs
Links:
dbSNP: rs751248523
NCBI 1000 Genomes Browser:
rs751248523
Molecular consequence:
  • NM_000520.6:c.929_930del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001318825.2:c.962_963del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NR_134869.3:n.969CT[1] - 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
SCV000809107Mayo Clinic Laboratories, Mayo Cliniccriteria provided, single submitter
Pathogenic
(Jun 27, 2018)
maternalclinical testing

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

SCV001362844Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jan 22, 2019)
germlineclinical testing

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

Citation Link,

SCV001588140Invitaecriteria provided, single submitter
Pathogenic
(Feb 6, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study.

Nestrasil I, Ahmed A, Utz JM, Rudser K, Whitley CB, Jarnes-Utz JR.

Mol Genet Metab. 2018 Feb;123(2):97-104. doi: 10.1016/j.ymgme.2017.12.432. Epub 2017 Dec 20.

PubMed [citation]
PMID:
29352662
PMCID:
PMC5832355
See all PubMed Citations (6)

Details of each submission

From Mayo Clinic Laboratories, Mayo Clinic, SCV000809107.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1maternalunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362844.1

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

Description

Variant summary: HEXA c.929_930delCT (p.Ser310CysfsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.Gln390X, p.Tyr427fsX5, p.Arg510X). The variant allele was found at a frequency of 5.3e-05 in 246224 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (5.3e-05 vs 0.0014), allowing no conclusion about variant significance. c.929_930delCT has been reported in the literature in individuals affected with Tay-Sachs Disease (Fernandes_1992, Nestrasil_2018, Utz_2015, Utz_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

From Invitae, SCV001588140.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Ser310Cysfs*13) in the HEXA gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs751248523, ExAC 0.02%). This variant has been observed in individual(s) with Tay-Sachs disease (PMID: 1302612). Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2021

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