rs104895366
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000431.4(MVK):c.709A>T(p.Thr237Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T237A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000431.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MVK | NM_000431.4 | c.709A>T | p.Thr237Ser | missense_variant | 8/11 | ENST00000228510.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MVK | ENST00000228510.8 | c.709A>T | p.Thr237Ser | missense_variant | 8/11 | 1 | NM_000431.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152110Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251486Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135920
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727240
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152110Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74298
ClinVar
Submissions by phenotype
Hyperimmunoglobulin D with periodic fever;C1867981:Porokeratosis 3, disseminated superficial actinic type;C1959626:Mevalonic aciduria Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 09, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 237 of the MVK protein (p.Thr237Ser). This variant is present in population databases (rs104895366, gnomAD 0.002%). This missense change has been observed in individual(s) with Mevalonate kinase deficiency (PMID: 16197847, 16835861, 21708801, 28814775, 31096039). ClinVar contains an entry for this variant (Variation ID: 97612). 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%. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2021 | Published functional studies demonstrate a significantly lowered MK enzyme activity (Rolland et al., 2005; Mandey et al., 2006); Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 25525159, 21708801, 16835861, 16435209, 21225694, 22038276, 22566169, 27213830, 21124859, 28814775, 31096039, 31589614) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
Hyperimmunoglobulin D with periodic fever Pathogenic:1Other:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 21, 2022 | ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PP3 supporting - |
not provided, no classification provided | literature only | Unité médicale des maladies autoinflammatoires, CHRU Montpellier | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at