ClinVar Miner

Submissions for variant NM_000431.4(MVK):c.1000G>A (p.Ala334Thr)

gnomAD frequency: 0.00006  dbSNP: rs104895317
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000688831 SCV000816455 pathogenic Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2024-01-03 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 334 of the MVK protein (p.Ala334Thr). This variant is present in population databases (rs104895317, gnomAD 0.02%). This missense change has been observed in individual(s) with mevalonate kinase deficiency and retinitis pigmentosa (PMID: 9334262, 10401001, 12563048, 16435210, 19786432, 24084495, 28095071). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11930). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MVK function (PMID: 9334262). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000688831 SCV002786434 pathogenic Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever 2022-02-13 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV003114187 SCV003800245 pathogenic not provided 2022-04-30 criteria provided, single submitter clinical testing The MVK c.1000G>A; p.Ala334Thr variant (rs104895317) is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with mevalonate kinase deficiency (Balgobind 2005, Brennenstuhl 2021, Gattorno 2009, Hinson 1997, Prietsch 2003, Siemiatkowska 2013). This variant is found in the non-Finnish European population with an allele frequency of 0.02% (22/128940 alleles) in the Genome Aggregation Database. The alanine at codon 334 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.862). Consistent with these predictions, functional studies indicate the variant protein has reduced enzymatic activity in vitro and in patient cells (Hinson 1997). Based on available information, this variant is considered to be pathogenic. References: Balgobind B et al. Retinitis pigmentosa in mevalonate kinase deficiency. J Inherit Metab Dis. 2005;28(6):1143-5. PMID: 16435210. Brennenstuhl et al. Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria. J Inherit Metab Dis. 2021 Sep;44(5):1272-1287. PMID: 34145613 Gattorno M et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009 Oct;124(4):e721-8. PMID: 1978643 Hinson DD et al. Identification of an active site alanine in mevalonate kinase through characterization of a novel mutation in mevalonate kinase deficiency. J Biol Chem. 1997 Oct 17;272(42):26756-60. PMID: 9334262. Prietsch V et al. Mevalonate kinase deficiency: enlarging the clinical and biochemical spectrum. Pediatrics. 2003 Feb;111(2):258-61. PMID: 12563048. Siemiatkowska AM et al. Mutations in the mevalonate kinase (MVK) gene cause nonsyndromic retinitis pigmentosa. Ophthalmology. 2013 Dec;120(12):2697-2705. PMID: 24084495.
OMIM RCV000012706 SCV000032941 pathogenic Mevalonic aciduria 2013-12-01 no assertion criteria provided literature only
OMIM RCV000074422 SCV000108438 pathogenic Hyperimmunoglobulin D with periodic fever 2013-12-01 no assertion criteria provided literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier RCV000074422 SCV000115913 not provided Hyperimmunoglobulin D with periodic fever no assertion provided not provided

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