rs121434394

chr11-101453068-G-A

Variant summary

Our verdict is Pathogenic. Variant got 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. 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:
  • 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:5
• Conservation: PhyloP100: 9.76

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a helix (size 36) in uniprot entity TRPC6_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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. Variant chr11-101453068-G-A is described in Lovd as [Pathogenic].

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
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). -

Focal segmental glomerulosclerosis 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 10, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2005	- -

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: 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;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs121434394; hg19: chr11-101323799;