NM_000520.6(HEXA):c.1496G>A (p.Arg499His) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 1, 2023
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:: RCV000520531.14

Allele description [Variation Report for NM_000520.6(HEXA):c.1496G>A (p.Arg499His)]

NM_000520.6(HEXA):c.1496G>A (p.Arg499His)

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.1496G>A (p.Arg499His)

HGVS:

NC_000015.10:g.72345476C>T
NG_009017.2:g.35704G>A
NM_000520.6:c.1496G>AMANE SELECT
NM_000520.6:c.1496G>A
NM_001318825.2:c.1529G>A
NP_000511.2:p.Arg499His
NP_001305754.1:p.Arg510His
NC_000015.10:g.72345476C>T
NC_000015.9:g.72637817C>T
NC_000015.9:g.72637817C>T
NM_000520.4:c.1496G>A
NM_000520.5:c.1496G>A
NR_134869.3:n.1281G>A
P06865:p.Arg499His
c.1496G>A (p.Arg499His)

Protein change:

R499H; ARG499HIS

Links:

UniProtKB: P06865#VAR_003244; OMIM: 606869.0010; dbSNP: rs121907956

NCBI 1000 Genomes Browser:

rs121907956

Molecular consequence:

NM_000520.6:c.1496G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318825.2:c.1529G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_134869.3:n.1281G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000331828	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Nov 6, 2015)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 14566483, 1833974, 2140574, 8490625 Citation Link,
SCV000617692	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 9, 2022)	germline	clinical testing	Citation Link,
SCV003917408	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000331828

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Pathogenic
(Nov 6, 2015)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000617692

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Nov 9, 2022)

germline

clinical testing

Citation Link,

SCV003917408

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Mar 1, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Different attenuated phenotypes of GM2 gangliosidosis variant B in Japanese patients with HEXA mutations at codon 499, and five novel mutations responsible for infantile acute form.

Tanaka A, Hoang LT, Nishi Y, Maniwa S, Oka M, Yamano T.

J Hum Genet. 2003;48(11):571-4. Epub 2003 Oct 18.

PubMed [citation]

PMID:: 14566483

Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease.

Triggs-Raine BL, Akerman BR, Clarke JT, Gravel RA.

Am J Hum Genet. 1991 Nov;49(5):1041-54.

PubMed [citation]

PMID:: 1833974
PMCID:: PMC1683266

See all PubMed Citations (4)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000331828.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

#	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		1	not provided	not provided	not provided

From GeneDx, SCV000617692.3

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

Description

Published functional studies demonstrate a damaging effect (retention of the Hex alpha-subunit in the ER and posterior degradation along with a lower value of the solvent-accessible surface area) (Paw et al., 1990); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26984043, 2140574, 1833974, 18490185, 29214523, 35936646, 34288098, 33240792)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV003917408.7

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

Description

HEXA: PP4:Strong, PM2, PM3, PM5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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