NM_001127453.2(GSDME):c.1193_1196dup (p.Ser399delinsArgTer) AND Autosomal dominant nonsyndromic hearing loss 5

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 15, 2018
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:: RCV000490372.5

Allele description [Variation Report for NM_001127453.2(GSDME):c.1193_1196dup (p.Ser399delinsArgTer)]

NM_001127453.2(GSDME):c.1193_1196dup (p.Ser399delinsArgTer)

Gene:

GSDME:gasdermin E [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

7p15.3

Genomic location:

Preferred name:

NM_001127453.2(GSDME):c.1193_1196dup (p.Ser399delinsArgTer)

HGVS:

NC_000007.14:g.24702823_24702826dup
NG_011593.1:g.60197_60200dup
NM_001127453.2:c.1193_1196dupMANE SELECT
NM_001127454.2:c.701_704dup
NM_004403.3:c.1193_1196dup
NP_001120925.1:p.Ser399delinsArgTer
NP_001120926.1:p.Ser235delinsArgTer
NP_004394.1:p.Ser399delinsArgTer
LRG_1428t1:c.1193_1196dup
LRG_1428:g.60197_60200dup
LRG_1428p1:p.Ser399delinsArgTer
NC_000007.13:g.24742442_24742445dup
NM_001127453.1:c.1193_1196dupATAG
NM_004403.2:c.1193_1196dupATAG

Links:

dbSNP: rs757421220

NCBI 1000 Genomes Browser:

rs757421220

Molecular consequence:

NM_001127453.2:c.1193_1196dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001127454.2:c.701_704dup - nonsense - [Sequence Ontology: SO:0001587]
NM_004403.3:c.1193_1196dup - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Autosomal dominant nonsyndromic hearing loss 5
Synonyms:: Deafness, autosomal dominant 5
Identifiers:: MONDO: MONDO:0010973; MedGen: C1832932; Orphanet: 90635; OMIM: 600994

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000267287	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 18, 2016)	germline	reference population	PubMed (2) [See all records that cite these PMIDs] 17868390, 25741868
SCV000916198	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Dec 15, 2018)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000267287

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 18, 2016)

germline

reference population

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

SCV000916198

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Uncertain significance
(Dec 15, 2018)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
East Asian	germline	unknown	2	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

A novel DFNA5 mutation, IVS8+4 A>G, in the splice donor site of intron 8 causes late-onset non-syndromic hearing loss in a Chinese family.

Cheng J, Han DY, Dai P, Sun HJ, Tao R, Sun Q, Yan D, Qin W, Wang HY, Ouyang XM, Yang SZ, Cao JY, Feng GY, Du LL, Zhang YZ, Zhai SQ, Yang WY, Liu XZ, He L, Yuan HJ.

Clin Genet. 2007 Nov;72(5):471-7. Epub 2007 Sep 14.

PubMed [citation]

PMID:: 17868390

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 Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267287.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	2	not provided	not provided	reference population	PubMed (2)

#	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		2	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000916198.1

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

Description

This variant results in a frameshift and is predicted to result in premature termination of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.

#	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: Apr 9, 2023

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