NM_000520.6(HEXA):c.748G>A (p.Gly250Ser) AND Tay-Sachs disease

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 21, 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:: RCV000675102.3

Allele description [Variation Report for NM_000520.6(HEXA):c.748G>A (p.Gly250Ser)]

NM_000520.6(HEXA):c.748G>A (p.Gly250Ser)

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.748G>A (p.Gly250Ser)

HGVS:

NC_000015.10:g.72350575C>T
NG_009017.2:g.30605G>A
NM_000520.6:c.748G>AMANE SELECT
NM_001318825.2:c.781G>A
NP_000511.2:p.Gly250Ser
NP_001305754.1:p.Gly261Ser
NC_000015.9:g.72642916C>T
NM_000520.4:c.748G>A
NM_000520.5:c.748G>A
NR_134869.3:n.790G>A

Protein change:

G250S

Links:

dbSNP: rs1057521137

NCBI 1000 Genomes Browser:

rs1057521137

Molecular consequence:

NM_000520.6:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318825.2:c.781G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_134869.3:n.790G>A - 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
SCV000800638	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Dec 14, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17259242, 7717398 Citation Link,
SCV003242132	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 21, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17259242, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000800638

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Uncertain significance
(Dec 14, 2017)

unknown

clinical testing

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

Citation Link,

SCV003242132

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 21, 2022)

germline

clinical testing

PubMed (2)
[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	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

Mutational analyses of Tay-Sachs disease: studies on Tay-Sachs carriers of French Canadian background living in New England.

Triggs-Raine B, Richard M, Wasel N, Prence EM, Natowicz MR.

Am J Hum Genet. 1995 Apr;56(4):870-9.

PubMed [citation]

PMID:: 7717398
PMCID:: PMC1801208

Evaluation of the risk for Tay-Sachs disease in individuals of French Canadian ancestry living in new England.

Martin DC, Mark BL, Triggs-Raine BL, Natowicz MR.

Clin Chem. 2007 Mar;53(3):392-8. Epub 2007 Jan 26.

PubMed [citation]

PMID:: 17259242

See all PubMed Citations (3)

Details of each submission

From Counsyl, SCV000800638.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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 Invitae, SCV003242132.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 250 of the HEXA protein (p.Gly250Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HEXA-related conditions. ClinVar contains an entry for this variant (Variation ID: 381668). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HEXA protein function. Experimental studies have shown that this missense change affects HEXA function (PMID: 17259242). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 30, 2024

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