Submissions for variant NM_000431.4(MVK):c.803T>C (p.Ile268Thr)

gnomAD frequency: 0.00018  dbSNP: rs104895304

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191109	SCV000245512	pathogenic	Mevalonic aciduria; Hyperimmunoglobulin D with periodic fever	2014-09-17	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [V377I] in a 21-year-old female with FTT in infancy, childhood developmental delay, hypermobile joints, muscle soreness, fatigue, obesity, recurrent infections, anemia, anxiety and depression, overbite, flat feet, unexplained fevers, family history of EDS. Variant pathogenic in recessive state; heterozygotes are carriers.
GeneDx	RCV000218157	SCV000279122	pathogenic	not provided	2023-06-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate decreased mevalonate kinase activity as compared with wild type (Houten et al., 1999); 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: 24088041, 11313768, 15536479, 29290516, 34525209, 34145613, 32060250, 23692791, 21425920, 10369262, 10417275, 11313769, 25897835, 24470648, 26116953, 26990548, 18839211, 10896296, 24084495, 31028937, 31474985, 31589614, 35753512, 19011501, 10369261)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000505909	SCV000604325	pathogenic	not specified	2016-11-16	criteria provided, single submitter	clinical testing
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000012710	SCV000680305	pathogenic	Mevalonic aciduria	2017-11-15	criteria provided, single submitter	clinical testing
Invitae	RCV000698175	SCV000826821	pathogenic	Mevalonic aciduria; Porokeratosis 3, disseminated superficial actinic type; Hyperimmunoglobulin D with periodic fever	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 268 of the MVK protein (p.Ile268Thr). This variant is present in population databases (rs104895304, gnomAD 0.03%). This missense change has been observed in individuals with mevalonate kinase deficiency and hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) (PMID: 10369261, 10401001, 10417275, 11313769, 19011501, 21425920, 23692791, 24470648, 26116953, 27142780, 27213830). ClinVar contains an entry for this variant (Variation ID: 11932). 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 not expected to disrupt MVK protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MVK function (PMID: 10369261, 10401001, 10417275). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000218157	SCV001746157	pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	MVK: PM3:Very Strong, PM2, PS3:Supporting
DASA	RCV002255091	SCV002526385	pathogenic	MVK-Related Disorders	2022-06-10	criteria provided, single submitter	clinical testing	The c.803T>C;p.(Ile268Thr) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clivar ID: 11932; PMID: 33917151; 24470648; 28359055; 24084495; 11313769) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 28359055) - PS3_moderate. The variant is present at low allele frequencies population databases (rs104895304– gnomAD 0.001709%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Ile268Thr) was detected in trans with a Pathogenic variant (PMID: 33917151; 24470648; 11313769) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 24084495) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262564	SCV002542345	pathogenic	Autoinflammatory syndrome	2020-01-01	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000012709	SCV002754539	pathogenic	Hyperimmunoglobulin D with periodic fever	2022-03-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002512988	SCV003685036	pathogenic	Inborn genetic diseases	2022-03-25	criteria provided, single submitter	clinical testing	The c.803T>C (p.I268T) alteration is located in exon 9 (coding exon 8) of the MVK gene. This alteration results from a T to C substitution at nucleotide position 803, causing the isoleucine (I) at amino acid position 268 to be replaced by a threonine (T). Based on the available evidence, the c.803T>C p.I268T alteration is classified as pathogenic for autosomal recessive mevalonate kinase deficiency; however, the association of this alteration with autosomal dominant MVK-related porokeratosis is unlikely. Based on data from gnomAD, the C allele has an overall frequency of 0.02% (44/282850) total alleles studied. The highest observed frequency was 0.03% (36/129164) of European (non-Finnish) alleles. This alteration has been reported as homozygous and compound heterozygous in multiple unrelated individuals with mevalonate kinase deficiency (Houten, 1999; Houten, 1999; Hinson, 1999; Cuisset, 2001; Sornsakrin, 2009; Gençpnar, 2012; Siemiatkowska, 2013; Jeyaratnam, 2016; Ter Haar, 2016; Dunn, 2018; Munoz, 2019; Correa, 2020; Brennenstuhl, 2021; Steiner, 2011). This amino acid position is well conserved in available vertebrate species. In two different studies involving patient cell lines, cells from two different patients (one homozygote and one compound heterozygote) showed reduced MKase enzymatic activity levels (Houten, 1999; Hinson, 1999). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000218157	SCV004226634	pathogenic	not provided	2023-02-15	criteria provided, single submitter	clinical testing	PP3, PP4, PM2, PM3, PS3, PS4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012709	SCV004240922	pathogenic	Hyperimmunoglobulin D with periodic fever	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: MVK c.803T>C (p.Ile268Thr) results in a non-conservative amino acid change in 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 0.00015 in 251464 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MVK causing Hyper-IgD syndrome (0.00015 vs 0.0056), allowing no conclusion about variant significance. c.803T>C has been reported in the literature in multiple individuals affected with Hyper-IgD syndrome (e.g. Houten_1999, Cuisset_2001, Simon_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity (Houten_1999). The following publications have been ascertained in the context of this evaluation (PMID: 10369261, 11313769, 16234278). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000012709	SCV000032944	pathogenic	Hyperimmunoglobulin D with periodic fever	2001-04-01	no assertion criteria provided	literature only
OMIM	RCV000012710	SCV000032945	pathogenic	Mevalonic aciduria	2001-04-01	no assertion criteria provided	literature only
Unité médicale des maladies autoinflammatoires, CHRU Montpellier	RCV000012709	SCV000115986	not provided	Hyperimmunoglobulin D with periodic fever		no assertion provided	not provided
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000218157	SCV001808261	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000218157	SCV001930874	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000218157	SCV001956678	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000218157	SCV001975859	pathogenic	not provided		no assertion criteria provided	clinical testing