Submissions for variant NM_000143.4(FH):c.823G>C (p.Gly275Arg)

dbSNP: rs1060499639

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000445614	SCV000537246	uncertain significance	Hereditary leiomyomatosis and renal cell cancer	2017-01-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000489286	SCV000577381	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22561013, 20618355, 37053010)
Ambry Genetics	RCV000494229	SCV000581652	pathogenic	Hereditary cancer-predisposing syndrome	2015-09-21	criteria provided, single submitter	clinical testing	The p.G275R variant (also known as c.823G>C), located in coding exon 6 of the FH gene, results from a G to C substitution at nucleotide position 823. The glycine at codon 275 is replaced by arginine, an amino acid with dissimilar properties. Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability resulting in decreased function (Mechaly AE, et al. FEBS Lett. 2012 Jun; 586(11):1606-11). In addition, the mutation p.G275E affecting this amino acid was described to segregate with several individuals of a family with multiple cutaneous and uterine leiomyomas (Smit DL, et al. Clin. Genet. 2011 Jan; 79(1):49-59). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000489286	SCV000829180	pathogenic	not provided	2024-07-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 275 of the FH protein (p.Gly275Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of leiomyomatosis and renal cell cancer (Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 393574). 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%. This variant disrupts the p.Gly275 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20618355). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.