ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.44A>C (p.Lys15Thr) (rs111033217)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211780 SCV000061517 pathogenic Rare genetic deafness 2017-04-13 criteria provided, single submitter clinical testing The p.Lys15Thr variant in GJB2 has been reported in the compound heterozygous st ate with another pathogenic variant in GJB2 in 5 individuals with hearing loss, and segregated in 4 affected relatives of two families (Wu 2002, Lim 2003, Welch 2007, LMM data). This variant has been identified in 2/109796 European chromoso mes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org ; dbSNP rs111033217); this frequency is low enough to be consistent with a reces sive carrier frequency for recessive hearing loss. In summary, this variant meet s criteria to be classified as pathogenic for autosomal recessive nonsyndromic h earing. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PM2.
Counsyl RCV000037855 SCV000220863 likely pathogenic Deafness, autosomal recessive 1A 2014-11-07 criteria provided, single submitter literature only
GeneDx RCV000490112 SCV000577003 pathogenic not provided 2021-05-11 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported as pathogenic in ClinVar but additional evidence is not available (Landrum et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12910486, 25388846, 17431919, 15253766, 16950989, 31160754, 12172394, 16380907, 12925341, 12865758, 16154643, 19235794, 26778469, 21465647, 17666888)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000037855 SCV000599724 likely pathogenic Deafness, autosomal recessive 1A 2017-05-09 criteria provided, single submitter clinical testing
Invitae RCV000490112 SCV001393336 pathogenic not provided 2020-09-02 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 15 of the GJB2 protein (p.Lys15Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with non-syndromic deafness in several individuals (PMID: 12172394, 17431919, 15253766). ClinVar contains an entry for this variant (Variation ID: 44752). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000490112 SCV001448748 pathogenic not provided 2019-03-22 criteria provided, single submitter clinical testing

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