NM_004004.6(GJB2):c.488T>C (p.Met163Thr) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jul 7, 2023
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:: RCV003323584.2

Allele description [Variation Report for NM_004004.6(GJB2):c.488T>C (p.Met163Thr)]

NM_004004.6(GJB2):c.488T>C (p.Met163Thr)

Gene:

GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.488T>C (p.Met163Thr)

HGVS:

NC_000013.11:g.20189094A>G
NG_008358.1:g.8882T>C
NM_004004.6:c.488T>CMANE SELECT
NP_003995.2:p.Met163Thr
LRG_1350t1:c.488T>C
LRG_1350:g.8882T>C
LRG_1350p1:p.Met163Thr
NC_000013.10:g.20763233A>G
NM_004004.5:c.488T>C
NM_004004.6(GJB2):c.488T>CMANE SELECT
p.Met163Thr

Protein change:

M163T

Links:

dbSNP: rs1273330603

NCBI 1000 Genomes Browser:

rs1273330603

Molecular consequence:

NM_004004.6:c.488T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004029843	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jul 7, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17666888, 30755392 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004029843

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jul 7, 2023)

germline

clinical testing

PubMed (2)
[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 multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort.

Putcha GV, Bejjani BA, Bleoo S, Booker JK, Carey JC, Carson N, Das S, Dempsey MA, Gastier-Foster JM, Greinwald JH Jr, Hoffmann ML, Jeng LJ, Kenna MA, Khababa I, Lilley M, Mao R, Muralidharan K, Otani IM, Rehm HL, Schaefer F, Seltzer WK, Spector EB, et al.

Genet Med. 2007 Jul;9(7):413-26.

PubMed [citation]

PMID:: 17666888

A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants.

Ji J, Shen L, Bootwalla M, Quindipan C, Tatarinova T, Maglinte DT, Buckley J, Raca G, Saitta SC, Biegel JA, Gai X.

Cold Spring Harb Mol Case Stud. 2019 Apr 1;5(2). doi:pii: a003756. 10.1101/mcs.a003756. Print 2019 Apr.

PubMed [citation]

PMID:: 30755392
PMCID:: PMC6549575

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004029843.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: GJB2 c.488T>C (p.Met163Thr) results in a non-conservative amino acid change located in the gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251140 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.488T>C has been reported in the literature as an uninformative genotype (i.e. zygosity not specified) in two alleles from a cohort of individuals undergoing genetic testing for autosomal recessive Non-Syndromic Hearing Loss (Putcha_2007). This report does not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30755392, 17666888). Three submitters, including the ClinGen Hearing Loss Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as 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

Last Updated: Dec 24, 2023

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