Submissions for variant NM_001830.4(CLCN4):c.2152C>T (p.Arg718Trp)

dbSNP: rs879255584

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Sydney Children's Hospital, SCHN	RCV000239734	SCV000245785	pathogenic	CLCN4-related disorder	2016-03-22	criteria provided, single submitter	clinical testing	De novo variant. Clinical phenotype consistent with case series of individuals with CLCN4 related disorder.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000816910	SCV000957439	pathogenic	not provided	2023-05-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN4 function (PMID: 27550844). 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 CLCN4 protein function. ClinVar contains an entry for this variant (Variation ID: 209116). This variant is also known as p.R624W. This missense change has been observed in individual(s) with CLCN4-related disease (PMID: 26633542, 27550844, 29314583). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 718 of the CLCN4 protein (p.Arg718Trp).
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000721130	SCV001976771	pathogenic	Intellectual disability, X-linked 49	2021-08-10	criteria provided, single submitter	clinical testing	PM1, PM2, PP2, PP3, PP5
3billion	RCV000721130	SCV002058687	pathogenic	Intellectual disability, X-linked 49	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novo in a similarly affected individual (PMID: 26633542, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000209116, PMID:26633542, PS1_S). A different missense change at the same codon has been reported to be associated with CLCN4 related disorder (ClinVar ID: VCV000521940, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.874, PP3_P). A missense variant is a common mechanism associated with Raynaud-Claes syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetic Services Laboratory, University of Chicago	RCV000816910	SCV002069088	pathogenic	not provided	2018-02-01	criteria provided, single submitter	clinical testing
Gene2Care/ Palmer Lab, University of New South Wales	RCV000721130	SCV002525721	pathogenic	Intellectual disability, X-linked 49	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000721130	SCV000852018	pathogenic	Intellectual disability, X-linked 49	2018-11-07	no assertion criteria provided	literature only
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252041	SCV002523491	uncertain significance	See cases	2020-02-03	flagged submission	clinical testing	ACMG classification criteria: PM2, PP2, PP5