ClinVar Genomic variation as it relates to human health

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.

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]

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.

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.

PS2,PM2_p,PP3

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.