rs869025541

Variant names:

• chr11-101504446-G-A
• rs869025541
• NM_004621.6:c.523C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_004621.6(TRPC6):​c.523C>T​(p.Arg175Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R175Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPC6 NM_004621.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 U:1
• Conservation: PhyloP100: 5.63

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-101504445-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 11-101504446-G-A is Pathogenic according to our data. Variant chr11-101504446-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222850.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.523C>T	p.Arg175Trp	missense_variant	Exon 2 of 13	ENST00000344327.8	NP_004612.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC6	ENST00000344327.8	c.523C>T	p.Arg175Trp	missense_variant	Exon 2 of 13	1	NM_004621.6	ENSP00000340913.3
TRPC6	ENST00000360497.4	c.523C>T	p.Arg175Trp	missense_variant	Exon 2 of 12	1		ENSP00000353687.4
TRPC6	ENST00000348423.8	c.523C>T	p.Arg175Trp	missense_variant	Exon 2 of 11	1		ENSP00000343672.4
TRPC6	ENST00000532133.5	c.523C>T	p.Arg175Trp	missense_variant	Exon 2 of 12	5		ENSP00000435574.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Focal segmental glomerulosclerosis 2 Pathogenic:3

Nov 29, 2022

Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.523C>T (p.Arg175Trp) TRPC6 variant has been reported in our laboratory in a 9-year-old girl with suspected focal segmental glomerulosclerosis associated with hypertensive crisis, requiring daily dialysis. Previous episode of 3 months of progressive decline with the last 3 weeks of refusal to eat and vomiting. Negative autoimmune study, proteinuria in the nephrotic range, hypocalcemia and hyperphosphatemia. Her father received a kidney transplant at 9 and 37 years of age. This variant is a de novo change in her father (healthy grandparents, aunt, and 15-year-old brother do not have the variant) and it has been previously reported as a de novo change in a patient with focal segmental glomerulosclerosis [PMID 28204945] and in two patients with steroid resistant nephrotic syndrome [PMID 28117080, 26668027]. In summary, c.523C>T TRPC6 variant meets our criteria to be classified as pathogenic based upon its absence from controls (gnomAD no frequency), computational evidence of pathogenicity (CADD, MutationTaster, SIFT, PolyPhen2), de novo occurrence in this family and specific patient´s phenotype. -

Feb 14, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as a de novo change in a patient with focal segmental glomerulosclerosis [PMID 28204945] -

Dec 01, 2023

Precision Medicine Center, Zhengzhou University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2,PM2_p,PP3 -

Nephrotic syndrome Pathogenic:2 Uncertain:1

Mar 22, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This individual is heterozygous for the c.523C>T p.(Arg175Trp) variant in the TRPC6 gene. To our knowledge, this variant has not been reported in any population databases (i.e. gnomAD, ExAC, ESP or dbSNP). This variant has been reported in three patients with steroid resistant nephrotic syndrome (Bierzynska et al 2017 Kidney Int 91:937-947 PMID: 28117080; Wang et al 2017 Pediatr Nephrol 32:1181-1192 PMID:28204945; Buscher et al 2016 Clin J Am Soc Nephrol 11:245-253 PMID: 26668027). The first two papers reported the variant as de novo/sporadic in the patient. In silico analysis (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster all predict this variant to be a likely pathogenic variant. This variant is considered to be likely pathogenic according to the ACMG guidelines. -

Nov 10, 2017

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 19, 2015

Blueprint Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jan 31, 2025

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 tryptophan, which is neutral and slightly polar, at codon 175 of the TRPC6 protein (p.Arg175Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with focal segmental glomerulosclerosis (PMID: 28204945, 33884742). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 222850). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TRPC6 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Jan 17, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including multiple apparent de novo cases. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging. -

TRPC6-related disorder Pathogenic:1

Apr 03, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TRPC6 c.523C>T variant is predicted to result in the amino acid substitution p.Arg175Trp. This variant has been reported in multiple individuals with focal segmental glomerulosclerosis (de novo in Wang et al. 2017. PubMed ID: 28204945; Bierzynska et al. 2017. PubMed ID: 28117080; de novo in Nagano et al. 2020. PubMed ID: 31937884; de novo in Hanafusa et al. 2021. PubMed ID: 33884742). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, different substitutions at the same codon (p.Arg175Gln and p.Arg175Gly) have been reported to be pathogenic for focal segmental glomerulosclerosis (Hofstra et al. 2013. PubMed ID: 23291369; Table S2, Park et al. 2020. PubMed ID: 32604935 ). The c.523C>T (p.Arg175Trp) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	1.9	L;.;L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.5	D;D;D;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.88
MutPred		0.58		Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);Loss of solvent accessibility (P = 0.0299);
MVP		0.90
MPC		1.0
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.81
gMVP		0.65

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: rs869025541; hg19: chr11-101375177; COSMIC: COSV60251095; COSMIC: COSV60251095;