NM_000520.6(HEXA):c.1073C>T (p.Thr358Met) AND Tay-Sachs disease

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 13, 2022
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:: RCV000706870.4

Allele description [Variation Report for NM_000520.6(HEXA):c.1073C>T (p.Thr358Met)]

NM_000520.6(HEXA):c.1073C>T (p.Thr358Met)

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.1073C>T (p.Thr358Met)

HGVS:

NC_000015.10:g.72348048G>A
NG_009017.2:g.33132C>T
NM_000520.6:c.1073C>TMANE SELECT
NM_001318825.2:c.1106C>T
NP_000511.2:p.Thr358Met
NP_001305754.1:p.Thr369Met
NC_000015.9:g.72640389G>A
NM_000520.4:c.1073C>T
NR_134869.3:n.1115C>T

Protein change:

T358M

Links:

dbSNP: rs552505619

NCBI 1000 Genomes Browser:

rs552505619

Molecular consequence:

NM_000520.6:c.1073C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001318825.2:c.1106C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_134869.3:n.1115C>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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Mus musculus glutamyl-prolyl-tRNA synthetase, mRNA (cDNA clone IMAGE:3980665), p...
Mus musculus glutamyl-prolyl-tRNA synthetase, mRNA (cDNA clone IMAGE:3980665), partial cds
gi|26252153|gb|BC040802.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000835944	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001461906	Natera, Inc.	no assertion criteria provided	Uncertain significance (Nov 18, 2017)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000835944

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 13, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001461906

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Nov 18, 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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000835944.2

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

Description

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 358 of the HEXA protein (p.Thr358Met). This variant is present in population databases (rs552505619, gnomAD 0.1%). 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: 582729). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

From Natera, Inc., SCV001461906.1

#	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: Sep 29, 2024

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