rs145192716
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_016011.5(MECR):โc.772C>Tโ(p.Arg258Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000806 in 1,613,706 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 Pathogenic (โ โ ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258L) has been classified as Benign.
Frequency
Consequence
NM_016011.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MECR | NM_016011.5 | c.772C>T | p.Arg258Trp | missense_variant | 7/10 | ENST00000263702.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MECR | ENST00000263702.11 | c.772C>T | p.Arg258Trp | missense_variant | 7/10 | 1 | NM_016011.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251270Hom.: 0 AF XY: 0.0000736 AC XY: 10AN XY: 135800
GnomAD4 exome AF: 0.0000821 AC: 120AN: 1461480Hom.: 0 Cov.: 30 AF XY: 0.0000688 AC XY: 50AN XY: 727014
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74368
ClinVar
Submissions by phenotype
Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 08, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Dec 21, 2023 | 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 dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities (MIM#617282). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 18 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2 and v3) (highest allele count: 587 heterozygotes, 2 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated zinc-binding dehydrogenase domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg258Leu) has been classified once as benign; however, with no supporting evidence (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic in ClinVar, and has been observed as compound heterozygous with loss of function variants in two families with childhood onset dystonia and other MECR-related features, and as homozygous in one family with adult onset optic atrophy (PMID: 27817865, 37734847, 31137067). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has segregated with disease in multiple families with affected individuals either compound heterozygous or homozygous for the variant, and unaffected heterozygous relatives (PMID: 27817865, 37734847, 31137067). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Studies in yeast and patient fibroblasts with this variant (both compound heterozygous and homozygous) showed decreased MECR protein levels. Yeast also showed impaired mitochondrial oxidative phosphorylation, however this was not reproduced in patient fibroblasts (PMID: 27817865, 37734847). Null flies rescued with this variant showed an age-related climbing defect indicative of neurodegeneration (PMID: 37653044). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU Mรผnchen | Jun 13, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | Kids Research, The Children's Hospital at Westmead | - | - - |
Optic atrophy 16 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 08, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 258 of the MECR protein (p.Arg258Trp). This variant is present in population databases (rs145192716, gnomAD 0.01%). This missense change has been observed in individual(s) with childhood-onset dystonia (PMID: 27817865, 31137067). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 374882). 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 MECR protein function with a positive predictive value of 80%. Studies have shown that this missense change alters MECR gene expression (PMID: 27817865). For these reasons, this variant has been classified as Pathogenic. - |
Optic atrophy;C0752202:Childhood Onset Dystonias Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | Dec 01, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at