Submissions for variant NM_016011.4(MECR):c.772C>T (p.Arg258Trp)

gnomAD frequency: 0.00006  dbSNP: rs145192716

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000415607	SCV001149831	pathogenic	Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities	2019-06-13	criteria provided, single submitter	clinical testing
Kids Research, The Children's Hospital at Westmead	RCV000415607	SCV001244726	pathogenic	Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities		criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865308	SCV002247275	pathogenic	not provided	2023-11-29	criteria provided, single submitter	clinical testing	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000415607	SCV005086744	pathogenic	Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities	2024-09-20	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 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
OMIM	RCV000415607	SCV000493968	pathogenic	Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities	2024-01-08	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755160	SCV000882982	likely pathogenic	Optic atrophy; Childhood Onset Dystonias	2016-12-01	no assertion criteria provided	research
OMIM	RCV003448300	SCV004175908	pathogenic	Optic atrophy 16	2024-01-08	no assertion criteria provided	literature only