NM_000520.6(HEXA):c.155C>A (p.Ser52Ter) AND Tay-Sachs disease

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 24, 2024
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:: RCV000780337.12

Allele description

NM_000520.6(HEXA):c.155C>A (p.Ser52Ter)

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.155C>A (p.Ser52Ter)

HGVS:

NC_000015.10:g.72375818G>T
NG_009017.2:g.5362C>A
NM_000520.6:c.155C>AMANE SELECT
NM_000520.6:c.155C>A
NM_001318825.2:c.155C>A
NP_000511.2:p.Ser52Ter
NP_001305754.1:p.Ser52Ter
NC_000015.9:g.72668159G>T
NM_000520.4:c.155C>A
NR_134869.3:n.197C>A

Protein change:

S52*

Links:

dbSNP: rs987036804

NCBI 1000 Genomes Browser:

rs987036804

Molecular consequence:

NR_134869.3:n.197C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000520.6:c.155C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001318825.2:c.155C>A - 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
SCV000917517	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 9, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22789865, 24767253, 22441121, 12180151 Citation Link,
SCV001211559	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 1833974, 8490625, 22441121, 28492532
SCV002024979	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 9, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002089761	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 17, 2017)	germline	clinical testing

Help

Summary from all submissions

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

Citations

PubMed

GM2 gangliosidoses in Spain: analysis of the HEXA and HEXB genes in 34 Tay-Sachs and 14 Sandhoff patients.

Gort L, de Olano N, Macías-Vidal J, Coll MA; Spanish GM2 Working Group..

Gene. 2012 Sep 10;506(1):25-30. Epub 2012 Jul 10.

PubMed [citation]

PMID:: 22789865

Assessment of a targeted resequencing assay as a support tool in the diagnosis of lysosomal storage disorders.

Fernández-Marmiesse A, Morey M, Pineda M, Eiris J, Couce ML, Castro-Gago M, Fraga JM, Lacerda L, Gouveia S, Pérez-Poyato MS, Armstrong J, Castiñeiras D, Cocho JA.

Orphanet J Rare Dis. 2014 Apr 25;9:59. doi: 10.1186/1750-1172-9-59.

PubMed [citation]

PMID:: 24767253
PMCID:: PMC4024120

See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917517.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: HEXA c.155C>A (p.Ser52X) 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. c.187G>T, p.Glu63X and c.1168C>T, p.Gln390X). The variant allele was found at a frequency of 1.2e-05 in 246232 control chromosomes. c.155C>A has been reported in the literature in individuals affected with Tay-Sachs Disease (Gort_2012, McGinniss_2002, Zampieri_2012). At least one patient tested in these studies had <10% enzyme activity reported in the publication. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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, SCV001211559.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Ser52*) 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 is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with Tay‚ÄìSachs disease (PMID: 22441121). ClinVar contains an entry for this variant (Variation ID: 379311). For these reasons, this variant has been classified as Pathogenic.

#	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 Revvity Omics, Revvity, SCV002024979.3

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

#	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 Natera, Inc., SCV002089761.1

#	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

Last Updated: Mar 16, 2024

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