Submissions for variant NM_018127.7(ELAC2):c.98G>T (p.Arg33Leu)

gnomAD frequency: 0.00006  dbSNP: rs771550822

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000543316	SCV000654582	uncertain significance	Combined oxidative phosphorylation defect type 17	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 33 of the ELAC2 protein (p.Arg33Leu). This variant is present in population databases (rs771550822, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with ELAC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 474569). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
GeneDx	RCV000786308	SCV002012708	uncertain significance	not provided	2021-09-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV004619342	SCV005119617	uncertain significance	Inborn genetic diseases	2024-05-15	criteria provided, single submitter	clinical testing	The c.98G>T (p.R33L) alteration is located in exon 1 (coding exon 1) of the ELAC2 gene. This alteration results from a G to T substitution at nucleotide position 98, causing the arginine (R) at amino acid position 33 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786308	SCV000925076	uncertain significance	not provided	2017-08-31	no assertion criteria provided	provider interpretation	p.Arg33Leu (c.98G>T) in the ELAC2 gene (NM_018127.6) Invitae classifies this variant as a variant of uncertain significance. Given that this gene is of unclear significance in causing adult-onset HCM, and the absence of case data in support of this variant's pathogenicity, 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"). The ELAC2 gene causes a subtype of oxidative phosphorylation deficiency (COXPD17) that manifests as severe infantile-onset HCM. This patient is an adult and has a single variant (of unclear significance) in this gene. Even the detection of a single pathogenic variant would be insufficient to be the cause of his disease. The variant has not been reported in the literature. Per the test report, "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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain." The variant was reported online in 8 of 93,025 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 7 of 37,816 individuals of European descent (MAF=0.009%) and 1 of 2,466 individuals of "other" descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.