Submissions for variant NM_004004.6(GJB2):c.388G>C (p.Gly130Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788498	SCV005398087	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be 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) (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM; PMID:17935238). (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (p.(Gly130Asp), 1 heterozygote, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (connexin domain; NCBI, PDB). (N) 0702 - Comparable variants have strong previous evidence for pathogenicity. Alternative changes p.(Gly130Ala) and p.(Gly130Val) have been reported as pathogenic/likely pathogenic in many patients with autosomal dominant or recessive deafness (ClinVar; Deafness Variation Database; PMIDs: 12792423, 31992338, 31419744). In addition, p.(Gly130Asp) has been reported in a patient with hearing loss but with inconsistent interpretations (Deafness Variation Database; PMID: 17666888). (P) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been previously reported for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Institute of Rare Diseases, West China Hospital, Sichuan University	RCV005052910	SCV005686690	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2025-01-09	criteria provided, single submitter	research	PM3;PM5;PM2_Supporting;PP3