rs762913101

Positions:

chr1-29202004-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_016011.5(MECR):c.695G>A(p.Gly232Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,614,044 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

MECR
NM_016011.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.66

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:

MECR (HGNC:):

MECR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

PP5

Variant 1-29202004-C-T is Pathogenic according to our data. Variant chr1-29202004-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-29202004-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MECR	NM_016011.5 linkuse as main transcript	c.695G>A	p.Gly232Glu	missense_variant	6/10	ENST00000263702.11	NP_057095.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MECR	ENST00000263702.11 linkuse as main transcript	c.695G>A	p.Gly232Glu	missense_variant	6/10	1	NM_016011.5	ENSP00000263702.6		Q9BV79-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251486

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00159

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:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2022	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 09, 2023	- -

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

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 08, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 21, 2024	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. -

MECR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2023

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. -

Mitochondrial disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 03, 2023

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. -

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

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

.;T

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Pathogenic

4.5

.;H

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-8.0

D;D

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

.;D

Vest4

0.98

MutPred

0.90

.;Gain of disorder (P = 0.0359);

MVP

0.92

MPC

0.59

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Other links and lift over