Submissions for variant NM_000143.4(FH):c.610C>A (p.His204Asn)

dbSNP: rs863223996

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196812	SCV000251465	uncertain significance	not provided	2014-11-14	criteria provided, single submitter	clinical testing	p.His204Asn (CAT>AAT): c.610 C>A in exon 5 of the FH gene (NM_000143.3). The H204N variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H204N variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H204N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense mutations in nearby residues (A194T, M195V, M195T, H196R, L211P) have been reported in association with hereditary leiomyomatosis and renal cell cancer (HLRCC), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in MITONUC-MITOP panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196812	SCV001209392	uncertain significance	not provided	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 204 of the FH protein (p.His204Asn). This variant is not present in population databases (gnomAD no frequency). 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: 214409). 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 not expected to disrupt FH protein function with a negative predictive value of 95%. 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	RCV002354553	SCV002655448	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The p.H204N variant (also known as c.610C>A), located in coding exon 5 of the FH gene, results from a C to A substitution at nucleotide position 610. The histidine at codon 204 is replaced by asparagine, an amino acid with similar properties. This amino acid position is well 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.
Baylor Genetics	RCV004567401	SCV005057772	uncertain significance	Fumarase deficiency	2023-12-29	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005396584	SCV006055370	uncertain significance	Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer	2023-04-28	criteria provided, single submitter	clinical testing