NM_000520.6(HEXA):c.748G>A (p.Gly250Ser) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 12, 2021
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:: RCV000443171.6

Allele description [Variation Report for NM_000520.6(HEXA):c.748G>A (p.Gly250Ser)]

NM_000520.6(HEXA):c.748G>A (p.Gly250Ser)

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.748G>A (p.Gly250Ser)

HGVS:

NC_000015.10:g.72350575C>T
NG_009017.2:g.30605G>A
NM_000520.6:c.748G>AMANE SELECT
NM_001318825.2:c.781G>A
NP_000511.2:p.Gly250Ser
NP_001305754.1:p.Gly261Ser
NC_000015.9:g.72642916C>T
NM_000520.4:c.748G>A
NM_000520.5:c.748G>A
NR_134869.3:n.790G>A

Protein change:

G250S

Links:

dbSNP: rs1057521137

NCBI 1000 Genomes Browser:

rs1057521137

Molecular consequence:

NM_000520.6:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318825.2:c.781G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_134869.3:n.790G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000521180	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 17, 2019)	germline	clinical testing	Citation Link,
SCV002064497	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 12, 2021)	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

SCV000521180

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 17, 2019)

germline

clinical testing

Citation Link,

SCV002064497

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 12, 2021)

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	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000521180.3

#	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; Enzymatic activity in a cell model demonstrated a decrease to 4% of WT.; Not observed in large population cohorts (Lek et al., 2016); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17259242, 7717398)

#	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 Genetic Services Laboratory, University of Chicago, SCV002064497.1

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

Description

DNA sequence analysis of the HEXA gene demonstrated a sequence change, c.748G>A, in exon 7 that results in an amino acid change, p.Gly250Ser. This sequence change is absent in the gnomAD population database. This sequence change does not appear to have been described in individuals with HEXA-related disorders. However, a different sequence change affecting the same amino acid residue (p.Gly250Asp) has been described in a family with juvenile onset Tay Sachs disease (PMID: 1301189). The p.Gly250Ser change affects a highly conserved amino acid residue located in a domain of the HEXA protein that is known to be functional. The p.Gly250Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies show p.Gly250Ser disrupts the activity of the HEXA protein (PMIDs: 7717398, 17259242). Collectively this evidence indicates p.Gly250Ser is likely pathogenic.

#	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

Last Updated: Sep 29, 2024

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