Submissions for variant NM_000126.4(ETFA):c.667C>T (p.Arg223Ter)

gnomAD frequency: 0.00004  dbSNP: rs769976586

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493941	SCV000582398	pathogenic	not provided	2019-05-03	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29096039, 31589614)
Illumina Laboratory Services, Illumina	RCV000779174	SCV000915694	uncertain significance	Multiple acyl-CoA dehydrogenase deficiency	2018-11-21	criteria provided, single submitter	clinical testing	The ETFA c.667C>T (p.Arg223Ter) variant is a stop-gained variant predicted to result in premature termination of the protein, which was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this disease.
Invitae	RCV000779174	SCV001376670	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg223*) in the ETFA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ETFA are known to be pathogenic (PMID: 16510302, 23785301). This variant is present in population databases (rs769976586, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with bilateral renal dysplasia and multiple renal cysts (PMID: 29096039). ClinVar contains an entry for this variant (Variation ID: 429752). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000779174	SCV002769537	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with recessive glutaric acidemia IIA (MIM#231680). (I) (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 10 heterozygotes, 0 homozygotes). (SP) 0701 – Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least nine NMD-predicted variants along the ETFA gene (Decipher, PMIDs: 18289905, 31268564). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported in a family with multiple affected pregnancies with bilateral renal dysplasia and renal cysts (PMID: 29096039). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV000779174	SCV003830740	likely pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2021-12-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000779174	SCV004194718	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2023-10-12	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001829411	SCV002089804	pathogenic	Glutaric acidemia type 2A	2020-11-17	no assertion criteria provided	clinical testing