Submissions for variant NM_004004.6(GJB2):c.585G>A (p.Met195Ile)

dbSNP: rs570552952

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000505530	SCV000599763	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2017-05-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857234	SCV002298906	likely pathogenic	not provided	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 195 of the GJB2 protein (p.Met195Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 29148562). This variant has been reported in individual(s) with clinical features of autosomal dominant non-syndromic deafness (PMID: 18941476, 20601923); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 438621). 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. This variant disrupts the p.Met195 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20497192, 24013081, 30146550, 33597575). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000505530	SCV005399289	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both deafness and skin conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 28428247). (I) 0108 - This gene is associated with both recessive and dominant disease. The autosomal dominant diseases are commonly associated with pathogenic missense variants. The autosomal recessive disease is associated with bi-allelic loss-of-function variants and includes missense and protein truncating variants (NIH Genetics Home Reference, PMID: 12792423). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID:31160754). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity can range from mild to profound with intrafamilial variability also commonly seen. Commonly, truncating variants are associated to a more severe hearing loss (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Alternative nucleotide changes, resulting in the same amino acid change are present in gnomAD v2 <0.01 (27 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2) (highest allele count: 8 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated connexin domain (DECIPHER). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Met195Leu) has been classified as likely pathogenic (ClinVar), and p.(Met195Thr) has also been classified likely pathogenic (ClinVar, Deafness Variation Database). Additionally, p.(Met195Val) has been classified as pathogenic, and likely pathogenic by an expert panel and has been identified compound heterozygous with another pathogenic variant in at least two unrelated families with non-syndromic hearing loss (ClinVar, Deafness Variation database, PMIDs: 33597575 and 24507663) (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant and two alternative nucleotide changes resulting in the same amino acid substitution have been classified as likely pathogenic and VUS (ClinVar, Deafness variation database), and has been reported as a single heterozygous variant in individuals with and without hearing loss (PMIDs: 29921236, 20601923, 18941476, 29148562). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign