Submissions for variant NM_018127.7(ELAC2):c.2342G>A (p.Arg781His)

gnomAD frequency: 0.00064  dbSNP: rs119484086

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470586	SCV000559558	pathogenic	Combined oxidative phosphorylation defect type 17	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 781 of the ELAC2 protein (p.Arg781His). This variant is present in population databases (rs119484086, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of ELAC2-related conditions (PMID: 31045291; Invitae; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 5058). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ELAC2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000523886	SCV000616709	likely pathogenic	not provided	2024-07-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are contradictory: some suggesting impaired mitochondrial enzymatic activity of ELAC2, and others suggesting mitochondrial enzymatic activity similar to wildtype (PMID: 31045291, 15863270, 16636667); Observed as heterozygous and segregating with disease in a single family with prostate cancer (PMID: 11175785); This variant is associated with the following publications: (PMID: 15892892, 18809514, 24082139, 12515253, 15317868, 12021166, 12569551, 19555350, 15593091, 11507049, 12522685, 12790786, 15863270, 12711671, 16636667, 16287462, 25326635, 31045291, 33314036, 34539450, 28569218, 34964002, 11175785)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000470586	SCV000680207	pathogenic	Combined oxidative phosphorylation defect type 17	2017-11-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000523886	SCV000802218	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing	PM3
Baylor Genetics	RCV000470586	SCV000807604	uncertain significance	Combined oxidative phosphorylation defect type 17	2017-09-01	criteria provided, single submitter	clinical testing	This mutation has been previously reported in association with prostate cancer. It was found twice in our laboratory in trans with loss-of-function mutations: in a 1-year-old male with global delays, hypotonia, dysmorphism, microcephaly, failure to thrive, hypertorphic cardiomyopathy requiring transplant, and abnormal respiratory chain studies; in a 2-year-old female with global delays, hearing loss, hypotonia, dysmorphism, short stature, hypertrophic cardiomyopathy, delayed myelination. Heterozygotes would be expected to be asymptomatic carriers.
Ambry Genetics	RCV002512804	SCV003722580	uncertain significance	Inborn genetic diseases	2021-07-30	criteria provided, single submitter	clinical testing	(Saoura, 2019) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000470586	SCV003831880	uncertain significance	Combined oxidative phosphorylation defect type 17	2020-04-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000523886	SCV004142276	likely pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ELAC2: PM3:Strong, PM2
OMIM	RCV000005361	SCV000025539	pathogenic	Prostate cancer, hereditary, 2	2001-02-01	no assertion criteria provided	literature only