Submissions for variant NM_016011.5(MECR):c.830+2dup

gnomAD frequency: 0.00006  dbSNP: rs756421370

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521566	SCV000616771	likely pathogenic	not provided	2017-08-09	criteria provided, single submitter	clinical testing	The c.830+2dupT variant in the MECR gene has been reported in two unrelated families segregating an autosomal recessive form of childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (Heimer et al., 2016). This variant destroys the canonical splice donor site in intron 7. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.830+2dupT variant is not observed at a significant frequency in large population cohorts and is not observed in the homozygous state in any individual within these cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.830+2dupT as a likely pathogenic variant.
Undiagnosed Diseases Network, NIH	RCV000626033	SCV000746648	pathogenic	Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities	2018-01-16	criteria provided, single submitter	clinical testing	Compound heterozygous variants, c.830+2dupT and c.-39G>C, were detected in this individual. The c.830+2dupT variant disrupts the splice donor consensus and has previously been reported as disease causing [PMID 27817865]. The c.-39G>C variant lies in the 5'UTR and has never been published to our knowledge. It is absent from large control databases. Whole exome and Sanger sequencing showed the mother is heterozygous for the c.830+2dupT variant and the father is heterozygous for the c.-39G>C variant. Whole exome and Sanger sequencing also showed the affected sibling is heterozygous for both variants in MECR. Our data indicate that the two variants in the MECR gene are in trans configuration (compound heterozygous) in this patient and the affected sibling.
Invitae	RCV000521566	SCV002214220	pathogenic	not provided	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the MECR gene. It does not directly change the encoded amino acid sequence of the MECR protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs756421370, gnomAD 0.3%). This variant has been observed in individual(s) with MECR-related conditions (PMID: 27817865, 32445240). It has also been observed to segregate with disease in related individuals. This variant is also known as c.830+2insT, c.830+2_830+3insT, IVS7+2dupT. ClinVar contains an entry for this variant (Variation ID: 449055). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MECR function (PMID: 27817865). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 7 skipping and partial intron inclusion and introduces a new termination codon (PMID: 27817865). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV003314605	SCV004014689	likely pathogenic	Mitochondrial disease	2023-03-03	criteria provided, single submitter	clinical testing	The MECR c.830+2dup variant occurs in a splice region and results in the duplication of a thymine following the consensus splice donor site. This variant has been reported in a compound heterozygous state with the c.695G>A (p.Gly232Glu) 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 cells from some individuals (PMID: 27817865). The c.830+2dup variant has also been reported in trans with a 5'UTR variant in an additional affected sibling pair (PMID: 31160820). The highest frequency of this allele in the Genome Aggregation Database is 0.003086 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). cDNA studies using RNA from patient cells have demonstrated that the c.830+2dup variant disrupts splicing, producing two mutant transcripts: one in which exon 7 is skipped and one with partial retention of intron 8 that results in the addition of 108 bp to the mRNA sequence (PMID: 27817865). These missplicing events would be expected to disrupt the catalytic domain and part of the cofactor binding domain. This variant was identified in a compound heterozygous state with the c.695G>A (p.Gly232Glu) variant and segregated with disease. Based on the available evidence, the c.830+2dup variant is classified as likely pathogenic for primary mitochondrial disease.
OMIM	RCV000626033	SCV000493966	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	RCV000755158	SCV000882980	likely pathogenic	Optic atrophy; Childhood Onset Dystonias	2016-12-01	no assertion criteria provided	research
GenomeConnect, ClinGen	RCV000626033	SCV000986727	not provided	Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities		no assertion provided	phenotyping only	Variant interpretted as Pathogenic and reported most recently on 01-16-2018 by Lab or GTR ID 505801. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.