Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001811037 | SCV000632448 | uncertain significance | not provided | 2022-05-18 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 491 of the FH protein (p.Tyr491His). This variant is present in population databases (rs749713004, gnomAD 0.003%). 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: 460345). 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 not expected to disrupt 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. |
| ARUP Laboratories, |
RCV001811037 | SCV001471844 | uncertain significance | not provided | 2020-03-25 | criteria provided, single submitter | clinical testing | The FH c.1471T>C; p.Tyr491His variant (rs749713004), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 460345). This variant is found in the general population with an overall allele frequency of 0.001 % (3 / 250,440 alleles) in the Genome Aggregation Database. The tyrosine at codon 491 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Tyr491His variant is uncertain at this time. |
| Ambry Genetics | RCV002395335 | SCV002700648 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-17 | criteria provided, single submitter | clinical testing | The p.Y491H variant (also known as c.1471T>C), located in coding exon 10 of the FH gene, results from a T to C substitution at nucleotide position 1471. The tyrosine at codon 491 is replaced by histidine, an amino acid with similar properties. This amino acid position is not 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. |
| Natera, |
RCV000528987 | SCV002094178 | uncertain significance | Fumarase deficiency | 2019-10-28 | no assertion criteria provided | clinical testing |