Submissions for variant NM_000431.4(MVK):c.1006G>A (p.Gly336Ser)

gnomAD frequency: 0.00001  dbSNP: rs104895358

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689451	SCV005185826	pathogenic	Mevalonic aciduria	2024-05-15	criteria provided, single submitter	clinical testing	Variant summary: MVK c.1006G>A (p.Gly336Ser) results in a non-conservative amino acid change located in the GHMP kinase, C-terminal domain (IPR013750) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251104 control chromosomes. c.1006G>A has been reported in the literature as homozygous or in the compound heteroztygous state with a pathogenic variant in multiple individuals affected with autosomal recessive Hyperimmunoglobulin D with periodic fever with or without Mevalonic aciduria (e.g. Martini_2009, Marcuzzi_2016, ter Haar_2016, Schlabe_2016, Papa_2017, Rodrigues_2020, Wang_2020). These data indicate that the variant is very likely to be associated with disease. 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: 19036780, 26935981, 29047407, 32252977, 27899390, 33042144, 27213830). ClinVar contains an entry for this variant (Variation ID: 97561). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005003459	SCV005632731	likely pathogenic	Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever	2024-05-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005003459	SCV005863102	uncertain significance	Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever	2024-08-01	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 336 of the MVK protein (p.Gly336Ser). This variant is present in population databases (rs104895358, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal recessive MVK-related conditions (PMID: 19786432, 26935981, 26986117, 27213830, 27899390, 33042144). ClinVar contains an entry for this variant (Variation ID: 97561). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MVK 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.
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083813	SCV000115915	not provided	Hyperimmunoglobulin D with periodic fever		no assertion provided	not provided
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	RCV000083813	SCV002573425	likely pathogenic	Hyperimmunoglobulin D with periodic fever	2022-05-01	no assertion criteria provided	clinical testing