Submissions for variant NM_000143.4(FH):c.1379A>G (p.Asn460Ser)

dbSNP: rs767253363

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527720	SCV000632443	uncertain significance	not provided	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 460 of the FH protein (p.Asn460Ser). This variant is present in population databases (rs767253363, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 460341). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FH protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV003159781	SCV003901000	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-11	criteria provided, single submitter	clinical testing	The p.N460S variant (also known as c.1379A>G), located in coding exon 9 of the FH gene, results from an A to G substitution at nucleotide position 1379. The asparagine at codon 460 is replaced by serine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV002527720	SCV003915187	uncertain significance	not provided	2022-10-10	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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596240	SCV005090903	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000536299	SCV002085292	uncertain significance	Fumarase deficiency	2020-09-22	no assertion criteria provided	clinical testing