Submissions for variant NM_001830.4(CLCN4):c.949G>A (p.Val317Ile)

dbSNP: rs1064796023

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484553	SCV000572387	pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect on channel function (Palmer et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31785789, 33504798, 19377476, 36385166)
Gene2Care/ Palmer Lab, University of New South Wales	RCV003333750	SCV002525724	likely pathogenic	Intellectual disability, X-linked 49	2022-05-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003278834	SCV003961702	likely pathogenic	Inborn genetic diseases	2023-03-28	criteria provided, single submitter	clinical testing	The c.949G>A (p.V317I) alteration is located in exon 9 (coding exon 7) of the CLCN4 gene. This alteration results from a G to A substitution at nucleotide position 949, causing the valine (V) at amino acid position 317 to be replaced by an isoleucine (I). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported as de novo in multiple individuals with neurodevelopmental disorders and/or features consistent with Raynaud-Claes syndrome (Turner, 2019; Martin, 2021; Palmer, 2023). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003333750	SCV005085900	pathogenic	Intellectual disability, X-linked 49	2024-09-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Raynaud-Claes syndrome (MIM#300114). However, toxic gain of function has also been observed (PMID: 36385166). (I) 0110 - This gene is associated with X-linked dominant disease. However, heterozygous females may be either affected (with mild to severe intellectual disability) or unaffected (PMID: 27550844). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change, p.(Val317Phe), has been reported as a VUS, and more recently, has been reported in the literature in an individual with a neurodevelopmental condition (PMID: 36385166). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported once as a VUS, however, it is more commonly as likely pathogenic and pathogenic (ClinVar). It has been reported in multiple individuals with intellectual disability and/or a developmental disorder, where at least two of these individuals had agenesis of the corpus callosum. The variant was reported as both inherited and de novo (PMID: 19377476, PMID: 31785789, PMID: 33504798, PMID: 30919572, PMID: 36385166). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Suma Genomics	RCV003333750	SCV005359931	likely pathogenic	Intellectual disability, X-linked 49		criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV001260685	SCV001437777	uncertain significance	Intellectual disability	2020-09-10	flagged submission	clinical testing