Submissions for variant NM_001609.4(ACADSB):c.303+3A>G

gnomAD frequency: 0.00001  dbSNP: rs1345480688

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522412	SCV000616631	pathogenic	not provided	2016-09-09	criteria provided, single submitter	clinical testing	The c.303+3A>G variant in the ACADSB gene has been reported previously in association with autosomal recessive short/branched-chain acyl-CoA dehydrogenase deficiency (SBCADD) when present in the homozygous state or when in trans with another disease-causing variant (Kanavin et al., 2007; Madsen et al., 2006). This variant is predicted to destroy the natural splice donor site in intron 3. Functional studies demonstrate that the c.303+3A>G variant causes complete exon skipping of exon 3 (Madsen et al., 2006). We interpret c.303+3A>G as a disease-causing variant
Baylor Genetics	RCV000009779	SCV001522353	pathogenic	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2019-10-30	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV000009779	SCV002987490	pathogenic	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change falls in intron 3 of the ACADSB gene. It does not directly change the encoded amino acid sequence of the ACADSB protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has been observed in individual(s) with SBCAD deficiency (PMID: 12837870, 16317551, 30730842). ClinVar contains an entry for this variant (Variation ID: 448980). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16317551). For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003419901	SCV004116570	pathogenic	ACADSB-related disorder	2023-02-09	criteria provided, single submitter	clinical testing	The ACADSB c.303+3A>G variant is predicted to interfere with splicing. This variant has been reported in the homozygous and compound heterozygous states in related and unrelated individuals with 2-Methylbutyryl-CoA dehydrogenase deficiency (Matern D et al 2003. PubMed ID: 12837870; Madsen PP et al 2005. PubMed ID: 16317551; Kanavin OJ et al 2007. PubMed ID: 17883863). An in vitro study (minigene assay) showed this variant causes exon skipping (Madsen PP et al 2005. PubMed ID: 16317551). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-124797366-A-G). This variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000009779	SCV004807701	likely pathogenic	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2024-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000009779	SCV005039700	pathogenic	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2024-03-19	criteria provided, single submitter	clinical testing	Variant summary: ACADSB c.303+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. Consensus agreement among computation tools predict no significant impact on normal splicing. At least one publication reports experimental evidence that this variant results in exon 3 skipping (Madsen_2006). The variant allele was found at a frequency of 4e-06 in 251176 control chromosomes (gnomAD). c.303+3A>G has been reported in the literature in homozygous and compound heterozygous individuals affected with Deficiency of 2-methylbutyryl-CoA Dehydrogenase (Matern_2003, Madsen_2006, Kanavin_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17883863, 16317551, 12837870). ClinVar contains an entry for this variant (Variation ID: 448980). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000009779	SCV000030000	pathogenic	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2006-02-01	no assertion criteria provided	literature only
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000009779	SCV003035479	uncertain significance	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2022-06-20	flagged submission	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000009779	SCV004808389	pathogenic	Deficiency of 2-methylbutyryl-CoA dehydrogenase	2023-05-12	no assertion criteria provided	clinical testing