Submissions for variant NM_000126.4(ETFA):c.52C>T (p.Arg18Ter)

gnomAD frequency: 0.00004  dbSNP: rs754202690

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000824641	SCV000965546	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg18*) 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 (rs754202690, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Acyl-CoA dehydrogenase deficiency (PMID: 16510302). ClinVar contains an entry for this variant (Variation ID: 666198). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001564261	SCV001787399	pathogenic	not provided	2023-03-14	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; This variant is associated with the following publications: (PMID: 25525159, 31980526, 30612563, 16510302)
Ambry Genetics	RCV002538204	SCV003747206	pathogenic	Inborn genetic diseases	2021-12-23	criteria provided, single submitter	clinical testing	The c.52C>T (p.R18*) alteration, located in exon 2 (coding exon 2) of the ETFA gene, consists of a C to T substitution at nucleotide position 52. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 18. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.01% (16/281070) total alleles studied. The highest observed frequency was 0.02% (6/30600) of South Asian alleles. Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000824641	SCV004194714	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-03-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000824641	SCV004803546	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-01-22	criteria provided, single submitter	clinical testing	Variant summary: ETFA c.52C>T (p.Arg18X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.6e-05 in 251152 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ETFA causing Glutaric Aciduria, Type 2a (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.52C>T has been reported in the literature in individuals affected with Glutaric Aciduria, Type 2a. (examples: Schiff_2006, Wang_2019). The following publications have been ascertained in the context of this evaluation (PMID: 16510302, 30612563). ClinVar contains an entry for this variant (Variation ID: 666198). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000824641	SCV005633289	likely pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-05-07	criteria provided, single submitter	clinical testing