NM_000520.6(HEXA):c.496del (p.Arg166fs) AND Tay-Sachs disease

Clinical significance:Pathogenic (Last evaluated: Oct 26, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001264519.1

Allele description [Variation Report for NM_000520.6(HEXA):c.496del (p.Arg166fs)]

NM_000520.6(HEXA):c.496del (p.Arg166fs)

Gene:
HEXA:hexosaminidase subunit alpha [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
15q23
Genomic location:
Preferred name:
NM_000520.6(HEXA):c.496del (p.Arg166fs)
HGVS:
  • NC_000015.10:g.72353145del
  • NG_009017.1:g.28038del
  • NG_009017.2:g.28038del
  • NM_000520.6:c.496delMANE SELECT
  • NM_001318825.2:c.529del
  • NP_000511.2:p.Arg166fs
  • NP_001305754.1:p.Arg177fs
  • NC_000015.9:g.72645486del
  • NM_000520.5:c.496delC
  • NR_134869.3:n.538del
Protein change:
R166fs
Molecular consequence:
  • NM_000520.6:c.496del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001318825.2:c.529del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NR_134869.3:n.538del - 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
SCV001442713Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Oct 26, 2020)
germlineclinical testing

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

Citation Link

Summary from all submissions

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

Citations

PubMed

Two mutated HEXA alleles in a Druze patient with late-infantile Tay-Sachs disease.

Drucker L, Hemli JA, Navon R.

Hum Mutat. 1997;10(6):451-7.

PubMed [citation]
PMID:
9401008

The Israeli national population program of genetic carrier screening for reproductive purposes. How should it be continued?

Zlotogora J.

Isr J Health Policy Res. 2019 Dec 16;8(1):73. doi: 10.1186/s13584-019-0345-1.

PubMed [citation]
PMID:
31839005
PMCID:
PMC6912952

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442713.1

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

Description

Variant summary: HEXA c.496delC (p.Arg166AlafsX33) 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. The variant was absent in 251210 control chromosomes. c.496delC has been reported in the literature in at-least one individual affected with Tay-Sachs Disease and has been subsequently observed within settings of numerous carrier screening programs (example, Drucker_1997, Zlotogara_2019). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of normal enzyme activity in obligate carriers at levels expected for this genotype and further supported by the absence of steady-state levels of mRNA (example, Drucker_1997). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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

Last Updated: Jun 14, 2021

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