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

gnomAD frequency: 0.00003  dbSNP: rs111033217

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211780	SCV000061517	pathogenic	Rare genetic deafness	2020-10-14	criteria provided, single submitter	clinical testing	The p.Lys15Thr variant in GJB2 has been reported in the compound heterozygous state with another pathogenic variant in GJB2 in at least 6 individuals with hearing loss, and segregated in 5 affected relatives of three families (Wu 2002 PMID: 12172394, Lim 2003 PMID: 12925341, Welch 2007 PMID: 17431919, LMM data). This variant has been identified in 3/111888 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033217); this frequency is low enough to be consistent with a recessive carrier frequency for recessive hearing loss. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing. ACMG/AMP Criteria applied: PM3_VeryStrong, PP1_Strong, PM2_Supporting.
Counsyl	RCV000037855	SCV000220863	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2014-11-07	criteria provided, single submitter	literature only
GeneDx	RCV000490112	SCV000577003	likely pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31970404, 12172394, 26778469, 21465647, 17666888, 12925341, 36048236, 12865758, 16154643, 16950989, 27340645, 25388846, 16380907, 12910486, 19235794, 15253766, 31160754, 19775242, 17431919, 36515421)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000037855	SCV000599724	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000490112	SCV001393336	pathogenic	not provided	2023-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 15 of the GJB2 protein (p.Lys15Thr). This variant is present in population databases (rs111033217, gnomAD 0.002%). This missense change has been observed in individual(s) with non-syndromic deafness (PMID: 12172394, 15253766, 17431919). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 44752). 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 expected to disrupt GJB2 protein function. 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
Fulgent Genetics, Fulgent Genetics	RCV002490513	SCV002811622	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2021-12-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000490112	SCV004010216	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	GJB2: PM3:Very Strong, PM2, PP1, PP3
Natera, Inc.	RCV000037855	SCV002086069	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-10-16	no assertion criteria provided	clinical testing