Submissions for variant NM_004453.4(ETFDH):c.1130T>C (p.Leu377Pro)

dbSNP: rs387907170

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000210651	SCV000263007	pathogenic	Inborn genetic diseases	2014-07-21	criteria provided, single submitter	clinical testing	The c.1130T>C (p.L377P) alteration is located in exon 10 (coding exon 10) of the ETFDH gene. This alteration results from a T to C substitution at nucleotide position 1130, causing the leucine (L) at amino acid position 377 to be replaced by a proline (P). Based on data from the NHLBI Exome Sequencing Project (ESP), the c.1130T>C alteration was not observed among 6,503 individuals tested (0.0%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). REFERENCES: Kryukov GV, et al. (2007) Am J Hum Genet 80:727-739. Tennessen JA, et al. (2012) Science 337(64):64-69. Reported in association with CoQ10 deficiency (Gempel (2007) Brain 130, 2037). This amino acid position is completely conserved in available vertebrate species. This alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Based on the available evidence, this alteration is classified as pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000578325	SCV000680215	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2017-10-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000578325	SCV001585880	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2023-06-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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 not expected to disrupt ETFDH protein function. ClinVar contains an entry for this variant (Variation ID: 31601). This missense change has been observed in individual(s) with multiple Acyl-CoA dehydrogenase deficiency (PMID: 17412732, 29339009, 29376578, 31331668). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 377 of the ETFDH protein (p.Leu377Pro). This variant is present in population databases (rs387907170, gnomAD 0.0009%).
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000578325	SCV001755408	likely pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2022-08-18	criteria provided, single submitter	clinical testing	PM1, PM2, PP3, PP5
Genome-Nilou Lab	RCV000578325	SCV001810410	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2021-07-22	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000578325	SCV002580865	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2022-06-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000578325	SCV004194865	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2023-12-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000578325	SCV005185680	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-05-16	criteria provided, single submitter	clinical testing	Variant summary: ETFDH c.1130T>C (p.Leu377Pro) 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 4e-06 in 251294 control chromosomes. c.1130T>C has been reported in the literature in multiple individuals affected with Glutaric Aciduria, Type 2c (e.g., Nilipour_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32007756). ClinVar contains an entry for this variant (Variation ID: 31601). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000578325	SCV005664662	pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-05-16	criteria provided, single submitter	clinical testing
OMIM	RCV000024305	SCV000045596	pathogenic	Glutaric acidemia iic, late-onset	2007-08-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001831605	SCV002084863	pathogenic	Glutaric acidemia type 2C	2020-09-11	no assertion criteria provided	clinical testing