rs121434394
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_004621.6(TRPC6):c.2683C>T(p.Arg895Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R895L) has been classified as Pathogenic.
Frequency
Consequence
NM_004621.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPC6 | NM_004621.6 | c.2683C>T | p.Arg895Cys | missense_variant | 13/13 | ENST00000344327.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPC6 | ENST00000344327.8 | c.2683C>T | p.Arg895Cys | missense_variant | 13/13 | 1 | NM_004621.6 | P1 | |
TRPC6 | ENST00000360497.4 | c.2518C>T | p.Arg840Cys | missense_variant | 12/12 | 1 | |||
TRPC6 | ENST00000348423.8 | c.2335C>T | p.Arg779Cys | missense_variant | 11/11 | 1 | |||
TRPC6 | ENST00000532133.5 | c.2449C>T | p.Arg817Cys | missense_variant | 12/12 | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461518Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727064
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 31, 2022 | For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects TRPC6 function (PMID: 15924139, 19129465, 23645677, 26892346). 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. ClinVar contains an entry for this variant (Variation ID: 6155). 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. This variant is not present in population databases (gnomAD no frequency). 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). - |
Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Focal segmental glomerulosclerosis 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2005 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 10, 2022 | - - |
Nephrotic syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | Jul 03, 2019 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at