NM_000520.6(HEXA):c.1178G>A (p.Arg393Gln) AND Tay-Sachs disease

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Sep 1, 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:: RCV000670578.4

Allele description [Variation Report for NM_000520.6(HEXA):c.1178G>A (p.Arg393Gln)]

NM_000520.6(HEXA):c.1178G>A (p.Arg393Gln)

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.1178G>A (p.Arg393Gln)

HGVS:

NC_000015.10:g.72346679C>T
NG_009017.2:g.34501G>A
NM_000520.6:c.1178G>AMANE SELECT
NM_001318825.2:c.1211G>A
NP_000511.2:p.Arg393Gln
NP_001305754.1:p.Arg404Gln
NC_000015.9:g.72639020C>T
NG_009017.1:g.34501G>A
NM_000520.4:c.1178G>A

Protein change:

R393Q

Links:

dbSNP: rs370266293

NCBI 1000 Genomes Browser:

rs370266293

Molecular consequence:

NM_000520.6:c.1178G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318825.2:c.1211G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000795447	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (Nov 16, 2017)	unknown	clinical testing	Citation Link,
SCV001461554	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV002117823	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000795447

Counsyl

criteria provided, single submitter

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

Uncertain significance
(Nov 16, 2017)

unknown

clinical testing

Citation Link,

SCV001461554

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 16, 2020)

germline

clinical testing

SCV002117823

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 1, 2022)

germline

clinical testing

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

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

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 Counsyl, SCV000795447.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001461554.1

#	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

From Invitae, SCV002117823.2

#	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 arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 393 of the HEXA protein (p.Arg393Gln). This variant is present in population databases (rs370266293, gnomAD 0.07%). 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: 554870). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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: Dec 24, 2023

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