Submissions for variant NM_000143.4(FH):c.947C>A (p.Ala316Asp)

dbSNP: rs863224002

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199702	SCV000251475	likely pathogenic	not provided	2018-03-08	criteria provided, single submitter	clinical testing	This variant is denoted FH c.947C>A at the cDNA level, p.Ala316Asp (A316D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCT>GAT). Using alternate nomenclature, this variant would be defined as FH Ala273Asp. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FH Ala316Asp was not observed in large population cohorts (Lek 2016). Although this variant is not located in a known functional domain, missense variants at several surrounding residues have been reported in hereditary leiomyomatosis and renal cell cancer (HLRCC) or fumarate hydratase deficiency kindreds and shown to cause decreased FH enzyme activity (Martinez-Mir 2003, Toro 2003, Pithukpakorn 2006, Marque 2010, Gardie 2011, Picaud 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence and internal clinical data, we consider FH Ala316Asp to be a likely pathogenic variant.
Ambry Genetics	RCV000494152	SCV000581643	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-06	criteria provided, single submitter	clinical testing	The p.A316D pathogenic mutation (also known as c.947C>A), located in coding exon 7 of the FH gene, results from a C to A substitution at nucleotide position 947. The alanine at codon 316 is replaced by aspartic acid, an amino acid with dissimilar properties. This variant has been detected in individuals satisfying diagnostic criteria for Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome, and functional analysis demonstrated 29% of FH activity compared to controls (Muller M et al. Clin Genet, 2017 Dec;92:606-615; Ambry internal data). Based on internal protein structure analysis, this variant is predicted to disrupt the FH protein binding interface (Picaud S et al. J Inherit Metab Dis, 2011 Jun;34:671-6; Mechaly AE et al. FEBS Lett., 2012 Jun;586:1606-11). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199702	SCV000825943	pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 316 of the FH protein (p.Ala316Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with features consistent with hereditary leiomyomatosis and renal cell cancer (PMID: 28300276; internal data). ClinVar contains an entry for this variant (Variation ID: 214416). 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 FH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 28300276). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003454493	SCV004187000	likely pathogenic	Hereditary leiomyomatosis and renal cell cancer	2023-07-05	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: 28300276, Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data].