rs121434394

Variant names:

• chr11-101453068-G-A
• rs121434394
• NM_004621.6:c.2683C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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. 14/22 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:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRPC6 NM_004621.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.76
• Publications: 43 publications found

Genes affected

TRPC6 (HGNC:12338): (transient receptor potential cation channel subfamily C member 6) The protein encoded by this gene forms a receptor-activated calcium channel in the cell membrane. The channel is activated by diacylglycerol and is thought to be under the control of a phosphatidylinositol second messenger system. Activation of this channel occurs independently of protein kinase C and is not triggered by low levels of intracellular calcium. Defects in this gene are a cause of focal segmental glomerulosclerosis 2 (FSGS2). [provided by RefSeq, Mar 2009]

TRPC6 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004621.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-101453067-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1344650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 11-101453068-G-A is Pathogenic according to our data. Variant chr11-101453068-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC6	NM_004621.6	c.2683C>T	p.Arg895Cys	missense_variant	Exon 13 of 13	ENST00000344327.8	NP_004612.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC6	ENST00000344327.8	c.2683C>T	p.Arg895Cys	missense_variant	Exon 13 of 13	1	NM_004621.6	ENSP00000340913.3
TRPC6	ENST00000360497.4	c.2518C>T	p.Arg840Cys	missense_variant	Exon 12 of 12	1		ENSP00000353687.4
TRPC6	ENST00000348423.8	c.2335C>T	p.Arg779Cys	missense_variant	Exon 11 of 11	1		ENSP00000343672.4
TRPC6	ENST00000532133.5	c.2449C>T	p.Arg817Cys	missense_variant	Exon 12 of 12	5		ENSP00000435574.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461518 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727064

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111802

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.000550 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Focal segmental glomerulosclerosis 2 Pathogenic:2

Jul 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TRPC6-related disorder Pathogenic:1

Jun 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Nephrotic syndrome Pathogenic:1

Jul 03, 2019

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
PhyloP100		9.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.3	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.84
MutPred		0.85		Loss of phosphorylation at S892 (P = 0.0589);.;.;.;
MVP		0.97
MPC		0.22
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.89
gMVP		0.81
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121434394; hg19: chr11-101323799;