Submissions for variant NM_004453.4(ETFDH):c.405+3A>G

dbSNP: rs796051965

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001329258	SCV001520644	likely pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-02-20	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001509240	SCV001715844	likely pathogenic	not provided	2020-09-21	criteria provided, single submitter	clinical testing	PS1, PM2, PP3
GeneDx	RCV001509240	SCV001983020	likely pathogenic	not provided	2024-12-10	criteria provided, single submitter	clinical testing	Identified with a second variant in ETFDH in an newborn who was admitted to the intensive care units; detailed clinical information and biochemical testing results were not reported (PMID: 28973083); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15669683, 28973083)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001329258	SCV002049281	likely pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2021-10-08	criteria provided, single submitter	clinical testing	The ETFDH c.405+3A>G variant (rs796051965) is reported in the literature in the compound heterozygous state with another truncating ETFDH variant in an individual affected with glutaric acidemia (Meng 2017). This variant is also reported in ClinVar (Variation ID: 1028248), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by disrupting the canonical splice donor site of intron 3, which is likely to negatively impact gene function. Additionally, another variant at this position (c.405+3A>T) has been reported in the compound heterozygous state with other pathogenic ETFDH variants in individuals with acyl-CoA dehydrogenation deficiency and is considered pathogenic (Olsen 2004). Based on available information, the c.405+3A>G variant is considered to be likely pathogenic. References: Meng et al. Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management. JAMA Pediatr. 2017 Dec 4;171(12):e173438. PMID: 28973083. Olsen RK et al. Lipid-storage myopathy and respiratory insufficiency due to ETFQO mutations in a patient with late-onset multiple acyl-CoA dehydrogenation deficiency. J Inherit Metab Dis. 2004;27(5):671-8. PMID: 15669683.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844286	SCV002103750	uncertain significance	not specified	2022-02-28	criteria provided, single submitter	clinical testing	Variant summary: ETFDH c.405+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict a significant impact on normal splicing: 2/4 predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.6e-06 in 151006 control chromosomes (gnomAD v3.1 genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.405+3A>G has been reported in the literature in a critically ill infant for whom a clinical exome sequencing was performed, however no phenotype details were provided (Meng_2017). This report does not provide unequivocal conclusions about association of the variant with Glutaric Aciduria, Type 2c. A different variant affecting the same nucleotide (c.405+3A>T) is reported in affected individuals (HGMD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as Likely pathogenic (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Revvity Omics, Revvity	RCV001329258	SCV003832284	uncertain significance	Multiple acyl-CoA dehydrogenase deficiency	2022-02-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001329258	SCV005664641	likely pathogenic	Multiple acyl-CoA dehydrogenase deficiency	2024-06-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004749658	SCV005366558	uncertain significance	ETFDH-related disorder	2024-08-08	no assertion criteria provided	clinical testing	The ETFDH c.405+3A>G variant is predicted to interfere with splicing. This variant has been reported in an individual diagnosed with multiple acyl-CoA dehydrogenase deficiency (MADD); however, clinical information for this patient was not available (Meng et al. 2017. PubMed ID: 28973083). An alternate substitution at the same nucleotide (c.405+3A>T, also referred to as IVS3+3A>T) has been reported along with a second ETFDH variant in two symptomatic individuals with MADD (Olsen et al. 2004. PubMed ID: 15669683; Henriques et al. 2019. PubMed ID: 31418342). This variant has not been reported in a large population database, indicating this variant is rare. This variant is predicted to alter splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751); however, the use of computer prediction programs is not equivalent to functional evidence. Of note, the alternate c.405+3A>T variant was shown to lead to defective splicing in an RNA study (Olsen et al. 2004. PubMed ID: 15669683). Although we suspect that the c.405+3A>G variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.