NM_000520.6(HEXA):c.1444G>A (p.Glu482Lys) AND Inborn genetic diseases

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 27, 2021
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:: RCV002512734.7

Allele description [Variation Report for NM_000520.6(HEXA):c.1444G>A (p.Glu482Lys)]

NM_000520.6(HEXA):c.1444G>A (p.Glu482Lys)

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.1444G>A (p.Glu482Lys)

HGVS:

NC_000015.10:g.72345528C>T
NG_009017.2:g.35652G>A
NM_000520.6:c.1444G>AMANE SELECT
NM_001318825.2:c.1477G>A
NP_000511.2:p.Glu482Lys
NP_001305754.1:p.Glu493Lys
NC_000015.9:g.72637869C>T
NM_000520.4:c.1444G>A
NM_000520.5:c.1444G>A
NR_134869.3:n.1229G>A
P06865:p.Glu482Lys

Protein change:

E482K; GLU482LYS

Links:

UniProtKB: P06865#VAR_003240; OMIM: 606869.0004; dbSNP: rs121907952

NCBI 1000 Genomes Browser:

rs121907952

Molecular consequence:

NM_000520.6:c.1444G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318825.2:c.1477G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_134869.3:n.1229G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003571847	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Aug 27, 2021)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 2970528, 8123671, 8328462, 8672428, 9694901, 11707436, 16088929, 16698036, 27682588 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003571847

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Aug 27, 2021)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

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

A point mutation in the coding sequence of the beta-hexosaminidase alpha gene results in defective processing of the enzyme protein in an unusual GM2-gangliosidosis variant.

Nakano T, Muscillo M, Ohno K, Hoffman AJ, Suzuki K.

J Neurochem. 1988 Sep;51(3):984-7.

PubMed [citation]

PMID:: 2970528

Classification of disorders of GM2 ganglioside hydrolysis using 3H-GM2 as substrate.

Novak A, Callahan JW, Lowden JA.

Biochim Biophys Acta. 1994 Mar 2;1199(2):215-23. Erratum in: Biochim Biophys Acta 1995 Apr 13;1243(3):557.

PubMed [citation]

PMID:: 8123671

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV003571847.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The c.1444G>A (p.E482K) alteration is located in exon 13 (coding exon 13) of the HEXA gene. This alteration results from a G to A substitution at nucleotide position 1444, causing the glutamic acid (E) at amino acid position 482 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (2/251424) total alleles studied. This alteration has been reported in patients with Tay-Sachs disease (Nakano, 1988; Montalvo, 2005). Based on internal structural analysis, this variant is highly destabilizing to the local structure (Novak, 1994; Hou, 1996; Hou, 1998; Hepbildikler, 2002; Lemieux, 2006). Enzymatic activity was undetectable in both cultured patient fibroblasts and cells transiently expressing p.E482K. In addition, p.E482K was severely misfolded and degraded by the proteosome (Brown, 1993; Dersh, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

#	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: May 1, 2024

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