Submissions for variant NM_004453.4(ETFDH):c.296G>A (p.Arg99His)

gnomAD frequency: 0.00001  dbSNP: rs376630579

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001378006	SCV001575477	likely pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2023-01-24	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg99 amino acid residue in ETFDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23700290, 24522293, 29336361). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 ETFDH protein function. ClinVar contains an entry for this variant (Variation ID: 1066888). This variant has not been reported in the literature in individuals affected with ETFDH-related conditions. This variant is present in population databases (rs376630579, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 99 of the ETFDH protein (p.Arg99His).
GeneDx	RCV001762662	SCV001999517	uncertain significance	not provided	2019-12-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-silico analysis, which includes splice predictors, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323872	SCV004028884	uncertain significance	not specified	2023-07-27	criteria provided, single submitter	clinical testing	Variant summary: ETFDH c.296G>A (p.Arg99His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251440 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.296G>A in individuals affected with Glutaric Aciduria, Type 2c and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.