Submissions for variant NM_016011.5(MECR):c.695G>A (p.Gly232Glu)

gnomAD frequency: 0.00002  dbSNP: rs762913101

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519749	SCV000616770	likely pathogenic	not provided	2022-01-13	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect as yeast transfected with G232E showed absence of protein lipoylation and protein expression (Heimer 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: 27817865, 32445240)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000519749	SCV002243009	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 232 of the MECR protein (p.Gly232Glu). This variant is present in population databases (rs762913101, gnomAD 0.2%). This missense change has been observed in individual(s) with childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (PMID: 27817865). 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: 374878). 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%. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV003314592	SCV004014686	likely pathogenic	Mitochondrial disease	2023-03-03	criteria provided, single submitter	clinical testing	The MECR c.695G>A (p.Gly232Glu) missense variant results in the substitution of glycine at amino acid position 232 with glutamine. This variant has been reported in a compound heterozygous state with the c.830+2dup variant in four individuals with features of primary mitochondrial disease from three families, at least two of whom had Jewish ancestry (PMID: 27817865; PMID: 32445240; PMID: 34052969). Fibroblasts from compound heterozygous individuals showed reduced MECR protein expression and reduced protein lipoylation. Reduced electron transport capacity was also observed in some cases (PMID: 27817865). The c.695G>A variant has also been reported in trans with a stop-gained variant in an additional affected individual (PMID: 27817865). The highest frequency of this allele in the Genome Aggregation Database is 0.001587 in the Ashkenazi Jewish population (version 2.1.1). This frequency is consistent with the increased prevalence of MECR-related primary mitochondrial disease among individuals with Ashkenazi Jewish ancestry (PMID: 31070877). Yeast complementation studies of this variant, which is located within the cofactor binding domain, demonstrated an impaired ability to rescue the lactate-dependent growth phenotype compared to wildtype. The c.695G>A variant also showed reduced protein expression/stability and impaired lipoylation when expressed in yeast (PMID: 27817865). This variant was identified in a compound heterozygous state with the c.830+2dup variant and segregated with disease. Based on the available evidence, the c.695G>A (p.Gly232Glu) variant is classified as likely pathogenic for primary mitochondrial disease.
Revvity Omics, Revvity	RCV000519749	SCV004238281	likely pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000415570	SCV005380451	pathogenic	Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities	2024-08-21	criteria provided, single submitter	clinical testing	Variant summary: MECR c.695G>A (p.Gly232Glu) results in a non-conservative amino acid change located in the Alcohol dehydrogenase-like, C-terminal domain (IPR013149) of 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 7.2e-05 in 251486 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MECR causing Dystonia, Childhood-Onset, With Optic Atrophy And Basal Ganglia Abnormalities, allowing no conclusion about variant significance. c.695G>A has been reported in the literature in multiple compound heterozygous individuals affected with Dystonia, Childhood-Onset, With Optic Atrophy And Basal Ganglia Abnormalities (e.g. Heimer_2016, Alves_2018, Baide-Mairena_2022, Gupta_2023). 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. The most pronounced variant effect results in impaired ability to rescue a lactate-dependent growth phenotype in a yeast complementation study and impaired lipoylation (Heimer_2016). The following publications have been ascertained in the context of this evaluation (PMID: 32445240, 34988976, 36262091, 27817865). ClinVar contains an entry for this variant (Variation ID: 374878). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000415570	SCV000493964	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	RCV000755156	SCV000882978	likely pathogenic	Optic atrophy; Childhood Onset Dystonias	2016-12-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004758009	SCV005367564	likely pathogenic	MECR-related disorder	2023-12-29	no assertion criteria provided	clinical testing	The MECR c.695G>A variant is predicted to result in the amino acid substitution p.Gly232Glu. This variant has been reported in the compound heterozygous state in multiple unrelated affected individuals, and functional studies support its pathogenicity (Heimer et al. 2016. PubMed ID: 27817865; Alves et al. 2020. PubMed ID: 32445240, supplementary data; Martin-Saavedra et al. 2021. PubMed ID: 34052969). Pathogenic variants in MECR have been associated with autosomal recessive childhood-onset dystonia, with optic atrophy and basal ganglia abnormalities (OMIM #617282). This variant is reported in 0.16% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-29528516-C-T). This variant is interpreted as likely pathogenic.