Submissions for variant NM_004004.6(GJB2):c.487A>G (p.Met163Val)

gnomAD frequency: 0.00009  dbSNP: rs80338949

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001092709	SCV000061522	uncertain significance	not provided	2022-06-30	criteria provided, single submitter	clinical testing	The p.Met163Val variant in GJB2 has been identified in >10 probands with non-syndromic hearing loss from several ethnic populations; however, a pathogenic variant on the second allele of GJB2 was not detected in any of these probands (Al-Qahtani 2010, Amorini 2015, Bayazit 2003, Bonyadi 2009, Bonyadi 2014, Chaleshtori 2002, Chaleshtori 2005, Dalamon 2005, Falah 2012, Gunther 2003, Janecke 2002, Mahdieh 2011, Marlin 2001, Padma 2009, Tang 2006, Yilmaz 2010). In two families with post-lingual progressive hearing loss described in one study, two parent-to-child segregations were reported for this variant suggesting that the variant may lead to autosomal dominant hearing loss (Falah 2012). However, the majority of probands in the other studies did not report autosomal dominant inheritance of hearing loss. Two other missense variants at the same amino acid position (p.Met163Leu and p.Met163Thr) have also been reported in individuals with hearing loss, and in vitro functional studies of the p.Met163Val and p.Met163Leu show an impact to the normal activity of the protein due to these variants (Bruzzone 2003, Matos 2008). This data suggests that variants at this amino acid position are not tolerated. The p.Met163Val variant has also been identified 10/16478 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80338949); however this frequency is not high enough to rule out pathogenicity. In summary, the presence of the p.Met163Val variant in several affected individuals and the functional data suggests a pathogenic role for the variant, however the clinical significance of this variant cannot be determined with certainty given the absence of a second pathogenic variant in heterozygous probands and limited segregation data. ACMG/AMP Criteria applied:BS1, PP3.
CeGaT Center for Human Genetics Tuebingen	RCV001092709	SCV001249345	uncertain significance	not provided	2023-01-01	criteria provided, single submitter	clinical testing	GJB2: PS4:Supporting
INGEBI, INGEBI / CONICET	RCV001257048	SCV001433599	uncertain significance	Nonsyndromic genetic hearing loss	2020-08-31	criteria provided, single submitter	clinical testing	Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the filtering allele frequency of c.487A>G, p.Met163Val variant in GJB2 gene is 0,05% (23/30604 South Asian alleles with 95%CI) from Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/) which meets the criteria to apply to PM2_Supporting rule. Computational evidence predicted a pathogenic effect of the mutation to the protein (REVELscore: 0.869) applying to PP3 criteria. The p.Met163Val change has been identified only in heterozygous state in several patients (PMID: 11493200, 14643477, 15964725, 12189487, 12872268). Besides, in two familial cases this variant segregate in two affected individuals and their affected fathers (PMID:22208444). So, this evidence is not enough to be counted. On the other hand, p.Met163Val change was identified in homozygous state in a control subject meeting BS2 rule (PMID: 20086291). Functional studies demonstrated a highly reduction of dye transfer of p.Met163Val mutant in HeLa cells (PMID:28428247). Besides, it was shown that this mutant was unable to form functional gap junction channels in Xenopus Laevis oocytes (PMID:12505163). Hence, PS3_Moderate criteria was applied. In summary, the clinical significance of this variant is currently uncertain (PM2_Supporting, PP3, PS3_Moderate, BS2).
GeneDx	RCV001092709	SCV001784037	uncertain significance	not provided	2024-03-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in the heterozygous state with no other GJB2 variant in multiple individuals with hearing loss in published literature (PMID: 11493200, 19929407, 12189487, 20086306); Published functional studies demonstrate a damaging effect on gap junction function (PMID: 28428247, 12505163); Observed in unaffected parents of children with hearing loss who were heterozygous for the variant in published literature (PMID: 28263784, 19715472); This variant is associated with the following publications: (PMID: 25388846, 19941053, 12505163, 20086291, 24529908, 22208444, 24158611, 12189487, 21996152, 14643477, 21388256, 22695344, 19929407, 15964725, 30989077, 19715472, 20086306, 16380907, 17041943, 12872268, 31620696, 34426522, 34335733, Chaleshtori2005[article], 33096615, 31569309, 21281533, 31412945, 37892203, 37106706, 36833326, 38378725, 11493200, 28428247, 28263784, 26096904)
Genome-Nilou Lab	RCV000020573	SCV001810444	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001787816	SCV002029256	uncertain significance	Autosomal dominant nonsyndromic hearing loss 3A	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037860	SCV002051362	uncertain significance	not specified	2021-12-24	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.487A>G (p.Met163Val) results in a conservative amino acid change located in the extracellular 2 domain (Tang_2006) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251140 control chromosomes, predominantly at a frequency of 0.00075 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss phenotype (0.00034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.487A>G has been reported in the literature as a VUS with a non-informative genotype (i.e., second allele not specified or heterozygous) for a recessive mode of inheritance among individuals with various forms of moderate non sensorineural hearing loss undergoing genetic evaluation in small and large sized gene panels for hearing loss (example, Marlin_2001, Janecke_2002, Bayazit_2003, Tang_2006, Hamid_2009, Padma_2009, Bonyadi_2009, Yilmaz_2010, Al-Qahtani_2010, Mahdieh_2011, Falah_2012, Leone_2017, Buonfiglio_2020, Xie_2021). At-least one individual with moderate hearing loss reported a homozygous genotype although no family history, co-segregation/co-occurrence was specified (Amorini_2015). One family where the variant was transmitted from a father with late onset hearing impairment to two affected siblings with early onset hearing loss reported a possible instance of autosomal dominant transmission with anticipation (Falah_2012). Another report speculates a role in digenic inheritance with synergistic heterozygosity for this variant and variants in the TMPRSS3 gene (Leone_2017). However, a firm conclusion regarding these atypical modes of inheritance remain speculative. These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Bruzzone_2003, Press_2017). The most pronounced variant effect results in a complete inability to form homotypic channels since the level of junctional conductance measured never exceeded background values (Bruzzone_2003) and impaired gap junction function (Press_2017). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as VUS (n=6) (likely pathogenic, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation and the prevailing interpretation even in most recent publications remains as VUS (example, Buonfiglio_2020). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001092709	SCV003510273	uncertain significance	not provided	2022-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 163 of the GJB2 protein (p.Met163Val). This variant is present in population databases (rs80338949, gnomAD 0.07%). This missense change has been observed in individual(s) with deafness (PMID: 11493200, 12189487, 21281533, 22208444, 26096904). ClinVar contains an entry for this variant (Variation ID: 21388). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. Experimental studies have shown that this missense change affects GJB2 function (PMID: 12505163, 28428247). 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.
Revvity Omics, Revvity	RCV001092709	SCV003816811	uncertain significance	not provided	2021-05-07	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000020573	SCV004175861	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-03-01	criteria provided, single submitter	clinical testing	The missense c.487A>G(p.Met163Val) variant in GJB2 gene has been reported previously in heterozygous state in multiple individuals affected with GJB2-related hearing loss (Smith et. al., 2016; Günther et. al., 2003). This variant has been observed to segregate with disease in related individuals (Falah et. al., 2012). Functional studies demonstrate a damaging effect on gap junction function, impacting GJB2 function (Press ER, et. al., 2017; Bruzzone R, et. al.,2003). The p.Met163Val variant has been reported with allele frequency of 0.01% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic. The amino acid change p.Met163Val in GJB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 163 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV001787816	SCV005073752	pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2024-05-08	criteria provided, single submitter	research	Pathogenic by Deafness Variation Database and autosomal dominant according to PMID: 37892203
GeneReviews	RCV000020573	SCV000041049	not provided	Autosomal recessive nonsyndromic hearing loss 1A		no assertion provided	literature only
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375209	SCV001571911	likely pathogenic	Hearing impairment	2021-04-12	flagged submission	clinical testing	PS1_Strong, PM2_Moderate, PM5_Moderate, PP3_Supporting