NM_001127453.2(GSDME):c.1349G>A (p.Arg450His) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 9, 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:: RCV002229980.7

Allele description [Variation Report for NM_001127453.2(GSDME):c.1349G>A (p.Arg450His)]

NM_001127453.2(GSDME):c.1349G>A (p.Arg450His)

Gene:

GSDME:gasdermin E [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p15.3

Genomic location:

Preferred name:

NM_001127453.2(GSDME):c.1349G>A (p.Arg450His)

HGVS:

NC_000007.14:g.24699168C>T
NG_011593.1:g.63853G>A
NM_001127453.2:c.1349G>AMANE SELECT
NM_001127454.2:c.857G>A
NM_004403.3:c.1349G>A
NP_001120925.1:p.Arg450His
NP_001120926.1:p.Arg286His
NP_004394.1:p.Arg450His
LRG_1428t1:c.1349G>A
LRG_1428:g.63853G>A
LRG_1428p1:p.Arg450His
NC_000007.13:g.24738787C>T
NM_004403.2:c.1349G>A

Protein change:

R286H

Links:

dbSNP: rs764724618

NCBI 1000 Genomes Browser:

rs764724618

Molecular consequence:

NM_001127453.2:c.1349G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127454.2:c.857G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004403.3:c.1349G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002508370	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 9, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 35114279, 28492532
SCV002759024	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 1, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002508370

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 9, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002759024

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jun 1, 2022)

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	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

Genetic profiles of non-syndromic severe-profound hearing loss in Chinese Hans by whole-exome sequencing.

Liu Y, Tan M, Cai L, Lv L, Chen Q, Chen W, Yang H, Xu Y.

Gene. 2022 Apr 20;819:146258. doi: 10.1016/j.gene.2022.146258. Epub 2022 Feb 1.

PubMed [citation]

PMID:: 35114279

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, SCV002508370.3

#	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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the DFNA5 protein (p.Arg450His). This variant is present in population databases (rs764724618, gnomAD 0.003%). This missense change has been observed in individual(s) with deafness (PMID: 35114279). ClinVar contains an entry for this variant (Variation ID: 359838). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DFNA5 protein function. 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

From GeneDx, SCV002759024.1

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

Description

Observed in an individual in published literature (Liu et al., 2022) who had a different genetic etiology for the phenotype, however, variant was inherited from a parent reported to have high frequency hearing loss; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35114279)

#	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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