Submissions for variant NM_000143.4(FH):c.1520T>C (p.Leu507Pro)

dbSNP: rs1425094515

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000597494	SCV001577113	pathogenic	not provided	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 507 of the FH protein (p.Leu507Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cutaneous and/or uterine leiomyomas (PMID: 12761039; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as L464P. ClinVar contains an entry for this variant (Variation ID: 501651). 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%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002395536	SCV002705312	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-18	criteria provided, single submitter	clinical testing	The p.L507P variant (also known as c.1520T>C), located in coding exon 10 of the FH gene, results from a T to C substitution at nucleotide position 1520. The leucine at codon 507 is replaced by proline, an amino acid with similar properties. This alteration was reported in the literature in a proband with multiple cutaneous leiomyomas and FH deficiency in lymphoplastoid cell lines (Alam NA et al. Hum Mol Genet. 2003 Jun;12(11):1241-52.; Alam NA et al. J Mol Diagn, 2005 Oct;7:437-43). In addition, this variant has been reported in other individuals with a personal and/or family history that is consistent with FH-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003336091	SCV004045439	likely pathogenic	Hereditary leiomyomatosis and renal cell cancer	2023-05-05	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: 12761039, Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 16237213]. This variant is expected to disrupt protein structure [Myriad internal data].
Eurofins Ntd Llc (ga)	RCV000597494	SCV000708102	uncertain significance	not provided	2017-05-09	flagged submission	clinical testing