NM_000520.6(HEXA):c.1424C>G (p.Pro475Arg) AND Tay-Sachs disease

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 19, 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:: RCV002015485.3

Allele description [Variation Report for NM_000520.6(HEXA):c.1424C>G (p.Pro475Arg)]

NM_000520.6(HEXA):c.1424C>G (p.Pro475Arg)

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.1424C>G (p.Pro475Arg)

HGVS:

NC_000015.10:g.72345548G>C
NG_009017.2:g.35632C>G
NM_000520.6:c.1424C>GMANE SELECT
NM_001318825.2:c.1457C>G
NP_000511.2:p.Pro475Arg
NP_001305754.1:p.Pro486Arg
NC_000015.9:g.72637889G>C
NR_134869.3:n.1209C>G

Protein change:

P475R

Links:

dbSNP: rs758829206

NCBI 1000 Genomes Browser:

rs758829206

Molecular consequence:

NM_000520.6:c.1424C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001318825.2:c.1457C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_134869.3:n.1209C>G - 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
SCV002286404	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 19, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31388111, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002286404

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 19, 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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of novel variants in a large cohort of children with Tay-Sachs disease: An initiative of a multicentric task force on lysosomal storage disorders by Government of India.

Mistri M, Mehta S, Solanki D, Kamate M, Gupta N, Kabra M, Puri R, Girisha K, Hariharan S, Nampoothiri S, Sheth F, Sheth J.

J Hum Genet. 2019 Oct;64(10):985-994. doi: 10.1038/s10038-019-0647-8. Epub 2019 Aug 6.

PubMed [citation]

PMID:: 31388111

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, SCV002286404.2

#	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 proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 475 of the HEXA protein (p.Pro475Arg). This variant is present in population databases (rs758829206, gnomAD 0.003%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 31388111). ClinVar contains an entry for this variant (Variation ID: 1496248). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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: Sep 29, 2024

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