Submissions for variant NM_004700.4(KCNQ4):c.842T>C (p.Leu281Ser)

dbSNP: rs80358278

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000006624	SCV001448747	pathogenic	Autosomal dominant nonsyndromic hearing loss 2A	2018-12-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001567939	SCV001791714	pathogenic	not provided	2020-01-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the L281S mutation leads to non-functional channels and improper trafficking of mutant channels to the cell surface with a dominant negative effect on WT channels (Kim et al., 2011; Gao et al., 2013); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10571947, 23776385, 18797286, 12408061, 26036578, 24616153, 11252765, 28802383, 25116015, 23399560, 21951272, 17033161, 23750663, 20966080, 22785243)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001567939	SCV003523271	pathogenic	not provided	2024-06-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 281 of the KCNQ4 protein (p.Leu281Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 10571947). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6246). 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 KCNQ4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNQ4 function (PMID: 23750663). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000006624	SCV004173231	pathogenic	Autosomal dominant nonsyndromic hearing loss 2A	2023-04-11	criteria provided, single submitter	clinical testing
OMIM	RCV000006624	SCV000026807	pathogenic	Autosomal dominant nonsyndromic hearing loss 2A	2011-01-14	no assertion criteria provided	literature only
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000006624	SCV000777818	pathogenic	Autosomal dominant nonsyndromic hearing loss 2A	2015-08-20	no assertion criteria provided	literature only