Submissions for variant NM_018127.7(ELAC2):c.1780C>G (p.Gln594Glu)

dbSNP: rs1435693717

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541060	SCV000654573	uncertain significance	Combined oxidative phosphorylation defect type 17	2022-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 594 of the ELAC2 protein (p.Gln594Glu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 474562). 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. 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.
Clinical Genomics Laboratory, Stanford Medicine	RCV003993669	SCV004812183	uncertain significance	Prostate cancer, hereditary, 2	2021-06-11	criteria provided, single submitter	clinical testing	The p.Gln594Glu variant in the ELAC2 gene has not been previously reported in association with disease. This variant has been identified in 1/111,544 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that the p.Gln594Glu variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Gln594Glu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; BP4]
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786127	SCV000924789	uncertain significance	not provided	2018-01-09	no assertion criteria provided	provider interpretation	This variant was identified in a heterozygous state in a patient with familial cardiomyopathy. Testing was performed at Invitae. SCICD Classification: Variant of uncertain significance (VUS) based on lack of case data, rarity in population databases, lack of genotype-phenotype correlation. The patient only has one heterozygous variant reported and the disease is autosomal recessive. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: 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. Case data (not including our patient): None ClinVar: not present Cases in the literature: None Segregation data: none reported Functional data: None reported In silico data (missense variants only): 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." Conservation data: The glutamine at codon 594 is weakly conserved across species. Nearby pathogenic variants at this codon or neighboring codons: None Population data: Highest MAF in European NF population: 0.0009113%. The variant was reported online in 1 of 121,107 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 1 of 54,866 individuals of European NF descent (MAF=0.0009113%.). 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. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).