ClinVar Miner

Submissions for variant NM_000431.4(MVK):c.802A>G (p.Ile268Val) (rs759997079)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213141 SCV000279121 likely pathogenic not provided 2015-03-13 criteria provided, single submitter clinical testing The I268V variant has been published previously in a patient diagnosed with hyper-IgD syndrome (Barron et al., 2013). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. I268V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. The Isoleucine residue at amino acid position 268 is highly conserved, and another missense mutation at the same position, I268T, has been previously reported in association with HIDS (Houten et al., 1999). Therefore, based on the currently available information, I268V is a candidate for a disease-causing mutation although, the possibility that it is a benign polymorphism cannot be completed excluded.
Invitae RCV001340239 SCV001534039 uncertain significance Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2020-04-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 268 of the MVK protein (p.Ile268Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs759997079, ExAC 0.001%). This variant has not been reported in the literature in individuals with MVK-related conditions. ClinVar contains an entry for this variant (Variation ID: 234380). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Ile268 amino acid residue in MVK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27142780, 27213830, 19011501, 11313769, 23692791, 24470648, 26116953, 21425920, 10369261, 10417275, 10401001). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

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