Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000681872 | SCV001589666 | pathogenic | not provided | 2024-07-20 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 895 of the TRPC6 protein (p.Arg895Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of focal segmental glomerulosclerosis (PMID: 15924139, 28921387; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6155). 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 TRPC6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TRPC6 function (PMID: 15924139, 19129465, 23645677, 26892346). This variant disrupts the p.Arg895 amino acid residue in TRPC6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21734084). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV000006530 | SCV002800221 | pathogenic | Focal segmental glomerulosclerosis 2 | 2024-06-05 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000006530 | SCV000026713 | pathogenic | Focal segmental glomerulosclerosis 2 | 2005-07-01 | no assertion criteria provided | literature only | |
| Gharavi Laboratory, |
RCV000681872 | SCV000809351 | pathogenic | not provided | 2018-09-16 | no assertion criteria provided | research | |
| Sydney Genome Diagnostics, |
RCV001328174 | SCV001449462 | pathogenic | Nephrotic syndrome | 2019-07-03 | no assertion criteria provided | clinical testing | This individual is heterozygous for the c.2683C>T p.(Arg895Cys) variant in the TRPC6 gene. The variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). This variant has been demonstrated to segregate with disease in a large pedigree with autosomal dominant focal segmental glomerulosclerosis (Reiser et al 2005 Nat Genet 37: 739-744). Multiple in vitro functional studies supported pathogenicity of this variant due to a gain of function of the TRPC ion channel (Reiser et al 2005; Schlondorff et al 2009 Am J Physiol Cell Physiol 296: C558-C569; Chiluiza et al 2013 J Biol Chem 288: 18407-18420). This variant is considered to be pathogenic according to the ACMG guidelines (Evidence used: PS3, PM2, PP1_Strong). |
| Prevention |
RCV004751205 | SCV005349752 | pathogenic | TRPC6-related disorder | 2024-06-27 | no assertion criteria provided | clinical testing | The TRPC6 c.2683C>T variant is predicted to result in the amino acid substitution p.Arg895Cys. This variant was reported to segregate in a large family with autosomal dominant focal segmental glomerulosclerosis (Reiser et al. 2005. PubMed ID: 15924139). This variant was also reported to occur de novo in a female patient with steroid resistant nephrotic syndrome (Nagano et al. 2020. PubMed ID: 31937884). Functional studies indicate this variant results in increased activity compared to the wild type protein, consistent with a gain-of-function mechanism (Reiser et al. 2005. PubMed ID: 15924139; Schlöndorff et al. 2009. PubMed ID: 19129465; Riehle et al. 2016. PubMed ID: 26892346). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. |