Submissions for variant NM_004453.4(ETFDH):c.250G>A (p.Ala84Thr)

gnomAD frequency: 0.00004  dbSNP: rs121964954

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224728	SCV000281570	pathogenic	not provided	2015-10-30	criteria provided, single submitter	clinical testing
Invitae	RCV000553294	SCV000631958	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 84 of the ETFDH protein (p.Ala84Thr). This variant is present in population databases (rs121964954, gnomAD 0.2%). This missense change has been observed in individuals with late-onset, riboflavine-responsive form of MADD (PMID: 19249206, 20370797, 21347544, 22013910, 24357026, 27000805, 27270537). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12028). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ETFDH function (PMID: 27935074). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000224728	SCV001814073	pathogenic	not provided	2022-01-27	criteria provided, single submitter	clinical testing	Functional studies in an A84T knock-in mouse model found this variant was associated with lower steady state levels of ETF:QO protein and increased acylcarnitine concentration in muscle that was riboflavin-dependent, consistent with findings in muscle cells from affected individuals (Xu J et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27060313, 20370797, 25119904, 24357026, 21347544, 22013910, 19249206, 27000805, 24522293, 19265687, 29961769, 29615056, 28950901, 31058673, 31852447, 32190638, 27935074, 32778825, 33639866, 32005694, 33589341, 29046209, 27270537, 30709034, 30232818)
Revvity Omics, Revvity	RCV000553294	SCV002022219	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2021-04-27	criteria provided, single submitter	clinical testing
3billion	RCV000553294	SCV002058808	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012028, PMID:19249206, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (3billion dataset, PM3_M). A different missense change at the same codon has been reported to be associated with ETFDH related disorder (PMID:23628458, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.886, 3CNET: 0.925, PP3_P). A missense variant is a common mechanism associated with Glutaric acidemia IIC (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000127, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Pediatric Department, Xiangya Hospital, Central South University	RCV003231099	SCV002760204	uncertain significance	See cases		criteria provided, single submitter	clinical testing	This variant was observed in compound heterozygosity with variant (c.2T>G)
Fulgent Genetics, Fulgent Genetics	RCV000553294	SCV002796479	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2022-02-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000553294	SCV004194765	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2023-10-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000553294	SCV004241078	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: ETFDH c.250G>A (p.Ala84Thr) 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 0.00014 in 251434 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ETFDH causing Glutaric Aciduria, Type 2c (0.00014 vs 0.0011), allowing no conclusion about variant significance. c.250G>A has been reported in the literature in multiple individuals affected with lateonset multiple acylcoenzyme A dehydrogenation deficiency, including as a homozygote or heterozygote phenotype without second variants reported (e.g. Liu_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence demonstrating an impact on protein function in Etfdh-(h)A84T knock-in mice, showing reduced protein levels in muscle and liver with vitamin B2 deficiency, and clinical and biochemical profiles similar to human patients affected with riboflavin-responsive multiple acylcoenzyme A dehydrogenation deficiency (e.g. Xu_2018). The following publications have been ascertained in the context of this evaluation (PMID: 27270537, 30232818). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic (n=7) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000012808	SCV000033048	pathogenic	Glutaric acidemia IIc	2010-12-01	no assertion criteria provided	literature only
SingHealth Duke-NUS Institute of Precision Medicine	RCV000553294	SCV000853129	likely pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2017-06-07	no assertion criteria provided	curation
Natera, Inc.	RCV000553294	SCV001452018	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing