Variant rs756421370 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_016011.5(MECR):c.830+2_830+3insT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,612,816 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

MECR
NM_016011.5 splice_region, intron

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 8.19

Variant links:

Genes affected

MECR (HGNC:19691): (mitochondrial trans-2-enoyl-CoA reductase) The protein encoded by this gene is an oxidoreductase that catalyzes the last step in mitochondrial fatty acid synthesis. Defects in this gene are a cause of childhood-onset dystonia and optic atrophy. [provided by RefSeq, Mar 2017]

MECR links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 1-29200513-T-TA is Pathogenic according to our data. Variant chr1-29200513-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECR	NM_016011.5 linkuse as main transcript	c.830+2_830+3insT		splice_region_variant, intron_variant		ENST00000263702.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECR	ENST00000263702.11 linkuse as main transcript	c.830+2_830+3insT		splice_region_variant, intron_variant		1	NM_016011.5	P1	Q9BV79-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

251190

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000794

AC:

116

AN:

1460622

Hom.:

Cov.:

AF XY:

0.0000840

AC XY:

AN XY:

726442

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00337

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000831

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 08, 2024	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jan 16, 2018	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. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2017	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. -

Mitochondrial disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 03, 2023

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. -

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.73

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.73

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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