Submissions for variant NM_004700.4(KCNQ4):c.785A>T (p.Asp262Val)

dbSNP: rs80358275

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000655887	SCV005086685	uncertain significance	Autosomal dominant nonsyndromic hearing loss 2A	2024-09-22	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with autosomal dominant deafness 2A (MIM#600101). The exact mechanism exerted by premature termination codons remains unknown. Dominant negative is unlikely, as these mutant proteins lack the C-terminal necessary for heteromultimer formation (PMID: 34622280). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and moderate conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in a region where missense variants cluster within the C-terminal end of the ion transport domain (DECIPHER). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An alternative change, p.(Asp262Gly), has been previously classified as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported in an individual with autosomal dominant nonsyndromic hearing loss but has been reported both without classification and as a VUS (PMIDs: 18941426, 32382995). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. CHO cells co-transfected with WT and p.(Asp262Val) had no measurable outward current compared to WT cells, indicating that the variant induced channel deficiency (PMID: 31995783). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000655887	SCV000777816	pathogenic	Autosomal dominant nonsyndromic hearing loss 2A	2015-08-20	no assertion criteria provided	literature only