Submissions for variant NM_000143.4(FH):c.405T>G (p.His135Gln)

gnomAD frequency: 0.00001  dbSNP: rs1298815479

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001751383	SCV001381039	likely pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 135 of the FH protein (p.His135Gln). This variant is present in population databases (no rsID available, gnomAD 0.009%). 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: 940083). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.His135 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15761418, 30741757; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001751383	SCV001996913	uncertain significance	not provided	2023-07-05	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: 15761418, 30741757)
Ambry Genetics	RCV002322024	SCV002631956	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-13	criteria provided, single submitter	clinical testing	The p.H135Q variant (also known as c.405T>G), located in coding exon 4 of the FH gene, results from a T to G substitution at nucleotide position 405. The histidine at codon 135 is replaced by glutamine, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001751383	SCV004218880	uncertain significance	not provided	2022-11-16	criteria provided, single submitter	clinical testing	The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000087 (3/34534 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using a bioinformatics tool for the prediction of the effect of amino acid changes on protein structure and function yielded a prediction that this variant is deleterious. Based on the available information, we are unable to determine the clinical significance of this variant.
Natera, Inc.	RCV001209597	SCV002085872	uncertain significance	Fumarase deficiency	2020-05-14	no assertion criteria provided	clinical testing