Submissions for variant NM_000431.4(MVK):c.613A>G (p.Asn205Asp)

gnomAD frequency: 0.00001  dbSNP: rs104895364

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001594835	SCV001827963	pathogenic	not provided	2024-06-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on mevalonate kinase activity (PMID: 16835861); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16835861, 29624229, 27387687, 34426522, 32822427, 32441320, 29451047, 34905135, 35158047)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857407	SCV002228760	pathogenic	Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever	2023-09-01	criteria provided, single submitter	clinical testing	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 expected to disrupt MVK protein function. ClinVar contains an entry for this variant (Variation ID: 97603). This missense change has been observed in individual(s) with autosomal recessive mevalonate kinase deficiency (PMID: 16835861, 25677409, 26986117, 29047407, 32822427). This variant is present in population databases (rs104895364, gnomAD 0.02%). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 205 of the MVK protein (p.Asn205Asp). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262662	SCV002542337	likely pathogenic	Autoinflammatory syndrome	2021-11-25	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001857407	SCV002806561	pathogenic	Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever	2024-03-28	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000083855	SCV005086196	pathogenic	Hyperimmunoglobulin D with periodic fever	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hyperimmunoglobulinemia D with periodic fever (MONDO#0009849). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial variability has been reported (PMID: 32822427). In addition, This gene may be associated with a spectrum of disease, including severe perinatal presentations with hydrops (PMID: 27012807). (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 8 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated GHMP kinases N terminal domain domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It as been reported in multiple affected individuals with period fever and/or immunodeficiency disorder (PMIDs: 16835861, 27387687, 29047407, 29624229, 32441320, 32822427). It is also classified as likely pathogenic/pathogenic by diagnostic laboratories in ClinVar. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767066	SCV005380873	pathogenic	Mevalonic aciduria	2024-08-08	criteria provided, single submitter	clinical testing	Variant summary: MVK c.613A>G (p.Asn205Asp) results in a conservative amino acid change located in the GHMP kinase N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251366 control chromosomes. c.613A>G has been reported in the literature in multiple individuals affected with Mevalonic aciduria in the compound heterozygous state. 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: 32822427, 33505305, 16835861, 27387687, 29451047). ClinVar contains an entry for this variant (Variation ID: 97603). Based on the evidence outlined above, the variant was classified as pathogenic.
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV004767066	SCV005873619	likely pathogenic	Mevalonic aciduria	2022-04-28	criteria provided, single submitter	clinical testing
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000083855	SCV000115960	not provided	Hyperimmunoglobulin D with periodic fever		no assertion provided	not provided