rs145192716

Variant names:

• chr1-29200574-G-A
• rs145192716
• NM_016011.5:c.772C>T
• MECR p.Arg258Trp

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM2 PP3 PP5

The NM_016011.5(MECR):​c.772C>T​(p.Arg258Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000806 in 1,613,706 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005086744: 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)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (0 hom.)
• Consequence: MECR NM_016011.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:1
• Conservation: PhyloP100: 3.39
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005086744: 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).; SCV005885698: The most pronounced variant effect results in about 30% of normal protein expression (Fiorini_2023). PMID: 37734847; SCV006585513: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 37734847).; SCV002247275: Studies have shown that this missense change alters MECR gene expression (PMID: 27817865).; SCV006075600: "Published functional studies suggest a damaging effect on protein function (PMID: 37734847)"
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767
• PP5: Variant 1-29200574-G-A is Pathogenic according to our data. Variant chr1-29200574-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 374882.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016011.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECR	NM_016011.5	MANE Select	c.772C>T	p.Arg258Trp	missense	Exon 7 of 10	NP_057095.4	Q9BV79-1
	MECR	NM_001349715.2		c.877C>T	p.Arg293Trp	missense	Exon 8 of 11	NP_001336644.1
	MECR	NM_001349716.2		c.856C>T	p.Arg286Trp	missense	Exon 8 of 11	NP_001336645.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MECR	ENST00000263702.11	TSL:1 MANE Select	c.772C>T	p.Arg258Trp	missense	Exon 7 of 10	ENSP00000263702.6	Q9BV79-1
	MECR	ENST00000883815.1		c.772C>T	p.Arg258Trp	missense	Exon 7 of 11	ENSP00000553874.1
	MECR	ENST00000944953.1		c.772C>T	p.Arg258Trp	missense	Exon 7 of 10	ENSP00000615012.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251270 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000821 AC: 120 AN: 1461480 Hom.: 0 Cov.: 30 AF XY: 0.0000688 AC XY: 50 AN XY: 727014

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000104 AC: 116 AN: 1111722

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74368

African (AFR) AF: 0.0000483 AC: 2 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000847 Hom.: 0

Bravo AF: 0.0000604

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	-	-	Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities (6)
3	-	-	not provided (3)
-	1	-	Dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities;C5882723:Optic atrophy 16 (1)
1	-	-	Optic atrophy 16 (1)
1	-	-	Optic atrophy;C0752202:Childhood Onset Dystonias (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.72
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs145192716;

hg19: chr1-29527086;