Submissions for variant NM_000143.4(FH):c.1255T>C (p.Ser419Pro)

gnomAD frequency: 0.00001  dbSNP: rs200004220

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078144	SCV000109982	likely pathogenic	not provided	2012-12-20	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000445624	SCV000537264	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2017-01-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000078144	SCV000544243	pathogenic	not provided	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 419 of the FH protein (p.Ser419Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) (PMID: 15937070; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1126T>C (p.Ser376Pro). ClinVar contains an entry for this variant (Variation ID: 92451). 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 FH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 16597677). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492881	SCV000581641	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	The p.S419P mutation (also known as c.1255T>C), located in coding exon 9 of the FH gene, results from a T to C substitution at nucleotide position 1255. The serine at codon 419 is replaced by proline, an amino acid with some similar properties. This alteration, also designated as S376P (1126T>C) in the literature, has been observed several individuals with a personal and/or family history that is consistent with HLRCC-related disease (Wei MH et al. J. Med. Genet. 2006 Jan;43(1):18-27; Sanz-Ortega J et al. Am J Surg Pathol. 2013 Jan;37:74-80; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Sema4, Sema4	RCV000492881	SCV002535539	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000445624	SCV004186966	likely pathogenic	Hereditary leiomyomatosis and renal cell cancer	2023-07-06	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15937070, 31831373, 26945337]. Functional studies indicate this variant impacts protein function [PMID: 16597677]. This variant is expected to disrupt protein structure [Myriad internal data].
PreventionGenetics, part of Exact Sciences	RCV004555536	SCV004739570	pathogenic	FH-related disorder	2024-01-12	criteria provided, single submitter	clinical testing	The FH c.1255T>C variant is predicted to result in the amino acid substitution p.Ser419Pro. This variant is alternately referred to as p.Ser376Pro using Legacy nomenclature. This variant has been reported in individuals and families with hereditary leiomyomatosis and renal cell cancer (HLRCC; Table 1, Figure 3, Family 4400, Wei et al. 2006. PubMed ID: 15937070; Pithukpakorn et al. 2006. PubMed ID: 16597677; Lehtonen et al. 2011. PubMed ID: 21404119; Table 1, Sanz-Ortega et al. 2013. PubMed ID: 23211287; Table S1, Scharnitz et al. 2023. PubMed ID: 36777509). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic and pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/92451/). This variant is interpreted as pathogenic for autosomal dominant and recessive FH-associated disorders.