NM_018127.7:c.2353C>T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_018127.7(ELAC2):c.2353C>T(p.Arg785Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,072 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 Uncertain significance (★).
Frequency
Consequence
NM_018127.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ELAC2 | NM_018127.7 | c.2353C>T | p.Arg785Trp | missense_variant | Exon 24 of 24 | ENST00000338034.9 | NP_060597.4 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 249040Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134826
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1458900Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 725924
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Combined oxidative phosphorylation defect type 17 Uncertain:1
This sequence change replaces arginine with tryptophan at codon 785 of the ELAC2 protein (p.Arg785Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ELAC2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
The following genes were evaluated for sequence changes and exonic deletions/duplications (ACTC1, ACTN2, BAG3, CAV3, CSRP3, DES, ELAC2, FHL1, GLA, LAMP2, MTO1, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, TCAP, TNNC1, TNNI3, TNNT2, TPM1, TTR, VCL). Sequencing identified p.Arg785Trp (c.2353C>T) in the ELAC2 gene. Given the absence of case data and the poor phenotype-gene match, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Given no other information about this variant, we can say that it is unlikely to be associated with the patient’s cardiomyopathy phenotype given that she only has one variant detected in this gene. The ELAC2 gene is associated with autosomal recessive combined oxidating phosphorylation deficiency. Recessive variants in ELAC2 have been associated with severe infantile-onset hypertrophic cardiomyopathy in 5 patients from 3 unrelated families (Haack et al 2013). These patients also had many features of a metabolic disorder including hypotonia, lactic acidosis and developmental delay. Per the test report and our own searches, there is no case data for this variant. This variant is not present in ClinVar. Of the reported pathogenic variants in ELAC2 in ClinVar, none of the pathogenic variants are in the same codon or nearby codons. Per the report, in silico analysis with PolyPhen-2 predicts the variant to be disease-causing. The arginine at codon 785 is conserved across species, as are neighboring amino acids. There is variation at codon 785 listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on 126,216 unrelated individuals of African, Asian, European, Latino descent. The data includes 126,216 exomes and 15,137 genomes (as of October 20, 2016). Specifically, it was found in 1 out of 56,043 individuals of European (Non-Finnish) descent. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at