ClinVar

Description

The p.S419L variant (also known as c.1256C>T), located in coding exon 9 of the FH gene, results from a C to T substitution at nucleotide position 1256. The serine at codon 419 is replaced by leucine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 10000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. While this specific alteration has not been reported in the literature to date, another alteration at the same codon, p.S419P (designated as S376P), segregated with disease in one HLRCC family in the literature (Wei, MH et al. J Med Genet. 2006 Jan;43(1):18-27). Based on the majority of available evidence to date, the p.S419L variant is likely to be pathogenic.