Submissions for variant NM_024009.3(GJB3):c.196_198del (p.Asp66del)

dbSNP: rs786200895

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000345579	SCV000339768	uncertain significance	not provided	2016-03-22	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000345579	SCV001144060	uncertain significance	not provided	2019-03-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000345579	SCV001147224	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000345579	SCV001772469	uncertain significance	not provided	2022-10-28	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; Published in vitro expression studies suggest a damaging effect; a portion of the mutant protein does not reach the cell membrane suggestive of an intracellular trafficking defect and cells shows altered gap junction function, while there was no evidence for an increased rate of cell death in contrast to GJB3 variants associated with skin disorders (Tattersall et al., 2009; Di et al., 2002); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19755382, 11179004, 12165562, 11758118, 12823303, 29044474, 19197336, 11309368)
Invitae	RCV000345579	SCV002225560	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	This variant, c.196_198del, results in the deletion of 1 amino acid(s) of the GJB3 protein (p.Asp66del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs777106179, gnomAD 0.04%). This variant has been observed in individual(s) with hearing impairment and/or neuropathy (PMID: 11309368, 35580552). ClinVar contains an entry for this variant (Variation ID: 6490). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GJB3 function (PMID: 12165562). 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243625	SCV002512635	uncertain significance	Hearing impairment	2021-06-23	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PM4 moderate, BS1 strong
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002468963	SCV002766454	uncertain significance	not specified	2022-11-20	criteria provided, single submitter	clinical testing	Variant summary: GJB3 c.196_198delGAC (p.Asp66del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.00014 in 251390 control chromosomes. This frequency does not allow conclusions about variant significance. c.196_198delGAC has been reported in the literature as a dominant mutation in at-least one family with sensorineural hearing loss and peripheral neuropathy (5 genotyped affected transmissions) where it showed both non-segregation (one reference allele transmission to a genotyped affected) and variable penetrance (an unaffected individual with the variant) (example, Lopez-Bigas_2001).These data indicate that the variant may be associated with disease although the authors suggest that other genetic modifiers or environmental factors could contribute to the overall phenotypic spectrum of manifesations. At least two publications report experimental evidence evaluating an impact on protein function evaluating defective channel formation by localization studies and dye transfer experiments, however, do not allow convincing conclusions about the variant effect (example, Di_2002, Tattersall_2009). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; Pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
OMIM	RCV000006863	SCV000027059	pathogenic	Deafness, autosomal dominant, with peripheral neuropathy	2001-04-15	no assertion criteria provided	literature only