NM_000520.6(HEXA):c.187G>T (p.Glu63Ter) AND Tay-Sachs disease

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Aug 31, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000586108.6

Allele description [Variation Report for NM_000520.6(HEXA):c.187G>T (p.Glu63Ter)]

NM_000520.6(HEXA):c.187G>T (p.Glu63Ter)

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.187G>T (p.Glu63Ter)

HGVS:

NC_000015.10:g.72375786C>A
NG_009017.2:g.5394G>T
NM_000520.6:c.187G>TMANE SELECT
NM_001318825.2:c.187G>T
NP_000511.2:p.Glu63Ter
NP_001305754.1:p.Glu63Ter
NC_000015.9:g.72668127C>A
NM_000520.4:c.187G>T
NR_134869.3:n.229G>T

Protein change:

E63*

Links:

dbSNP: rs759092928

NCBI 1000 Genomes Browser:

rs759092928

Molecular consequence:

NR_134869.3:n.229G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000520.6:c.187G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001318825.2:c.187G>T - nonsense - [Sequence Ontology: SO:0001587]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000697166	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jun 9, 2016)	germline	clinical testing	LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000792481	Counsyl	no assertion criteria provided	Likely pathogenic (Jun 26, 2017)	unknown	clinical testing
SCV002089760	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Aug 17, 2017)	germline	clinical testing
SCV003450471	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 31, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 1833974, 8490625, 28492532

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.

Triggs-Raine BL, Akerman BR, Clarke JT, Gravel RA.

Am J Hum Genet. 1991 Nov;49(5):1041-54.

PubMed [citation]

PMID:: 1833974
PMCID:: PMC1683266

Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients.

Akli S, Chomel JC, Lacorte JM, Bachner L, Kahn A, Poenaru L.

Hum Mol Genet. 1993 Jan;2(1):61-7. Erratum in: Hum Mol Genet 1993 Apr;2(4):496.

PubMed [citation]

PMID:: 8490625

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697166.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Variant summary: The HEXA c.187G>T (p.Glu63X) variant results in a premature termination codon, predicted to cause a truncated or absent HEXA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP), nor has it been, to our knowledge, reported in affected individuals via publications and/or reputable clinical laboratories/databases. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Probable Disease Variant/Likely Pathogenic," until additional information becomes available.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000792481.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002089760.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV003450471.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Glu63*) in the HEXA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant has not been reported in the literature in individuals affected with HEXA-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 496010).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 14, 2024

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