chr10-133370670-T-C
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PP3_ModeratePP5_Very_StrongBS1_Supporting
The NM_004092.4(ECHS1):āc.176A>Gā(p.Asn59Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000496 in 1,613,442 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 (ā ā ).
Frequency
Consequence
NM_004092.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152266Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000360 AC: 9AN: 249932Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135538
GnomAD4 exome AF: 0.0000520 AC: 76AN: 1461058Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 39AN XY: 726800
GnomAD4 genome AF: 0.0000262 AC: 4AN: 152384Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74522
ClinVar
Submissions by phenotype
Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency Pathogenic:3
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogeic with strong evidence (ClinVar ID:VCV000218890.5, PMID:28429146, 26251176, PS1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000036, PM2). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous in at least one similarly affected unrelated individual (PMID:28429146, 26251176; 3billion dataset). Missense changes are a common disease-causing mechanism (PP2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.712, 3Cnet: 0.973, PP3). Patient's phenotype is considered compatible with Mitochondrial Short-Chain Enoyl-CoA Hydratase Deficiency (3billion dataset, PP4). Therefore, this variant is classified aslikely pathogenic according to the recommendation of ACMG/AMP guideline. -
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not provided Pathogenic:2
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 59 of the ECHS1 protein (p.Asn59Ser). This variant is present in population databases (rs201865375, gnomAD 0.02%). This missense change has been observed in individuals with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (PMID: 26000322, 26251176, 28429146). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218890). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ECHS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ECHS1 function (PMID: 26251176). For these reasons, this variant has been classified as Pathogenic. -
Published functional studies demonstrate that N59S results in an unstable ECHS1 protein (Yamada et al., 2015); 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: 31967322, 31016024, 33163364, 26000322, 32013919, 33139125, 28429146, 34426522, 34667719, 33574353, 32901917, 26251176) -
ECHS1-related disorder Pathogenic:1
The ECHS1 c.176A>G variant is predicted to result in the amino acid substitution p.Asn59Ser. This variant has been reported in the compound heterozygous state in multiple individuals with ECHS1-deficiency (see for example, Haack et al. 2015. PubMed ID: 26000322; Supplemental Table, Ogawa et al. 2020. PubMed ID: 31967322; Kuwajima et al. 2021. PubMed ID: 34667719). This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD, and has been consistently classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/218890/). Given the evidence, we interpret this variant as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at