NM_000520.6(HEXA):c.1A>T (p.Met1Leu) AND Tay-Sachs disease

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 12, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003502538.2

Allele description [Variation Report for NM_000520.6(HEXA):c.1A>T (p.Met1Leu)]

NM_000520.6(HEXA):c.1A>T (p.Met1Leu)

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.1A>T (p.Met1Leu)

HGVS:

NC_000015.10:g.72375972T>A
NG_009017.2:g.5208A>T
NM_000520.6:c.1A>TMANE SELECT
NM_001318825.2:c.1A>T
NP_000511.2:p.Met1Leu
NP_001305754.1:p.Met1Leu
NC_000015.9:g.72668313T>A
NR_134869.3:n.43A>T

Protein change:

M1L

Links:

dbSNP: rs121907965

NCBI 1000 Genomes Browser:

rs121907965

Molecular consequence:

NM_000520.6:c.1A>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_001318825.2:c.1A>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000520.6:c.1A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318825.2:c.1A>T - missense variant - [Sequence Ontology: SO:0001583]
NR_134869.3:n.43A>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004297651	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 1532289, 21796138, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004297651

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 12, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Six novel deleterious and three neutral mutations in the gene encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals.

Mules EH, Hayflick S, Miller CS, Reynolds LW, Thomas GH.

Am J Hum Genet. 1992 Apr;50(4):834-41.

PubMed [citation]

PMID:: 1532289
PMCID:: PMC1682641

Identification of two HEXA mutations causing infantile-onset Tay-Sachs disease in the Persian population.

Haghighi A, Rezazadeh J, Shadmehri AA, Haghighi A, Kornreich R, Desnick RJ.

J Hum Genet. 2011 Sep;56(9):682-4. doi: 10.1038/jhg.2011.78. Epub 2011 Jul 28.

PubMed [citation]

PMID:: 21796138

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004297651.1

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

Description

This sequence change affects the initiator methionine of the HEXA mRNA. The next in-frame methionine is located at codon 193. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with hexosaminidase A deficiency (PMID: 1532289, 21796138). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 496858). 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

Last Updated: Sep 29, 2024

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