Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000083720 | SCV003443428 | uncertain significance | Familial Mediterranean fever | 2022-03-27 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 640 of the MEFV protein (p.Ile640Met). This variant is present in population databases (rs104895115, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with MEFV-related conditions. ClinVar contains an entry for this variant (Variation ID: 97468). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003987359 | SCV004804517 | uncertain significance | not specified | 2024-01-12 | criteria provided, single submitter | clinical testing | Variant summary: MEFV c.1920C>G (p.Ile640Met) results in a conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249068 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1920C>G has been reported in the literature in at least one individual affected with Familial Mediterranean Fever, in cis with another p.R635H variant, with no second variant in trans reported (e.g. Canete_2007). This co-occurrence of the variant with MEFV c.1958G>A, R653H, scored as pathogenic by our lab, provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31411330, 17665427). ClinVar contains an entry for this variant (Variation ID: 97468). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. |
| Unité médicale des maladies autoinflammatoires, |
RCV000083720 | SCV000115812 | not provided | Familial Mediterranean fever | no assertion provided | not provided |