Submissions for variant NM_004453.4(ETFDH):c.1001T>C (p.Leu334Pro)

gnomAD frequency: 0.00003  dbSNP: rs377686388

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723385	SCV000233073	pathogenic	not provided	2014-12-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000180601	SCV000756265	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 334 of the ETFDH protein (p.Leu334Pro). This variant is present in population databases (rs377686388, gnomAD 0.006%). This missense change has been observed in individuals with multiple acyl-CoA dehydrogenase deficiency (PMID: 12359134, 17584774). ClinVar contains an entry for this variant (Variation ID: 199094). 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: 22611163). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000180601	SCV000893658	likely pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000723385	SCV001783941	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	Expression studies found that L334P is associated with profoundly decreased ETF-QO protein levels and enzyme activities compared to wild-type and that there was no significant improvement in activity in response to increasing riboflavin levels (Cornelius et al. 2012); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12359134, 17584774, 22611163, 28263315, 31980526, 31904027)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000180601	SCV002570772	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2022-07-28	criteria provided, single submitter	clinical testing	Variant summary: ETFDH c.1001T>C (p.Leu334Pro) 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 2.4e-05 in 251366 control chromosomes. c.1001T>C has been reported in the literature in multiple individuals affected with Glutaric Aciduria, Type 2c (examples: Goodman_2002, Olsen_2007). These data indicate that the variant is very likely to be associated with disease. Expression studies showed that the variant results in profoundly reduced amount of protein amount and activity, with no significant response to increasing concentrations of riboflavin in culture media (Cornelius_2012). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000180601	SCV004194774	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-03-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004975312	SCV005587718	pathogenic	Inborn genetic diseases	2024-10-25	criteria provided, single submitter	clinical testing	The c.1001T>C (p.L334P) alteration is located in exon 9 (coding exon 9) of the ETFDH gene. This alteration results from a T to C substitution at nucleotide position 1001, causing the leucine (L) at amino acid position 334 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.003% (8/282776) total alleles studied. The highest observed frequency was 0.014% (1/7222) of Other alleles. This alteration was detected in the homozygous state, and in conjunction with another alteration in ETFDH, in multiple individuals with ETFDH-related glutaric acidemia II (Olsen, 2007; Ambrose, 2022; Goodman, 2002). This amino acid position is well conserved in available vertebrate species. In an assay testing ETFDH function, this variant showed a functionally abnormal result (Cornelius, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Natera, Inc.	RCV001826924	SCV002084858	pathogenic	Glutaric acidemia type 2C	2020-06-22	no assertion criteria provided	clinical testing