ClinVar Miner

Submissions for variant NM_000243.2(MEFV):c.1341G>C (p.Lys447Asn) (rs756322372)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000398473 SCV000329421 uncertain significance not provided 2016-09-01 criteria provided, single submitter clinical testing The K447N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. K447N was not observed in approximately 6400 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 K447N 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 not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001044845 SCV001208665 uncertain significance Familial Mediterranean fever 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 447 of the MEFV protein (p.Lys447Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs756322372, ExAC 0.003%). This variant has not been reported in the literature in individuals with MEFV-related conditions. ClinVar contains an entry for this variant (Variation ID: 279849). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Illumina Clinical Services Laboratory,Illumina RCV001044845 SCV001277727 uncertain significance Familial Mediterranean fever 2017-05-24 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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