Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000493972 | SCV000581631 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-07-26 | criteria provided, single submitter | clinical testing | The p.D341E pathogenic mutation (also known as c.1023T>G), located in coding exon 7 of the FH gene, results from a T to G substitution at nucleotide position 1023. The aspartic acid at codon 341 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been observed in at least two unrelated individuals with a personal and/or family history that is consistent with HLRCC-related disease (Ambry internal data). Based on internal structural analysis, this variant decreases structural stability (Ajalla Aleixo MA et al. FEBS J, 2019 05;286:1925-1940). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is not well conserved in available vertebrate species. 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 |
RCV002515398 | SCV000958781 | pathogenic | not provided | 2023-06-22 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 341 of the FH protein (p.Asp341Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) (Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 214382). 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. This variant disrupts the p.Asp341 amino acid residue in FH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21051878, 21304509, 22528940, 24684806). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. |