ClinVar Genomic variation as it relates to human health

The ACADSB c.303+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.303+1G>A variant has been reported in one study in which it was found in a homozygous state in two individuals with acyl-CoA dehydrogenase deficiency, oneof whom was symptomatic and the other asymptomatic newborn (Alfardan et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.000931 in the European American population of the Exome Sequencing Project. Based on the potential impact of splice donor variants and the clinical evidence, the c.303+1G>A variant is classified as likely pathogenic for acyl-CoA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1.

Variant summary: ACADSB c.303+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: One 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 0.00025 in 251174 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADSB causing Deficiency of 2-methylbutyryl-CoA Dehydrogenase (0.00025 vs 0.0011), allowing no conclusion about variant significance. c.303+1G>A has been reported in the literature in two homozygous individuals, an asymptomatic infant and a symptomatic individual, both with Deficiency of 2-methylbutyryl-CoA Dehydrogenase(Alfardan_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 20547083). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as pathogenic/likely pathogenic (n=7) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

The c.303+1G>A variant in ACADSB has been reported in the homozygous state in 2 individual with short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency; both showed the biochemical phenotype but only one showed clinical symptoms (Alfardan 2010 PMID: 20547083). It has also been reported in the homozygous state in 2 siblings without clinical symptoms (Spedicati 2021 PMID: 33727708). It has been identified in 0.056% (628/1127804) of European (non-Finnish) chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Computational prediction tools and conservation analyses are consistent with pathogenicity. Biallelic loss-of-function of the ACADSB gene is an established disease mechanism in autosomal recessive SBCAD deficiency. SBCAD deficiency results in a biochemical phenotype that be detected from birth; however, the clinical significance of this is unclear. 90% of individuals with SBCAD deficiency have no clinical symptoms, and the remaining 10% may display developmental delay and/or neurological disorders. These 10% of individuals may represent extreme end of the clinical spectrum or coincidental findings (Porta 2019 PMID: 30730842, Alfardan 2010 PMID: 20547083). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive SBCAD deficiency. ACMG/AMP Criteria applied: PVS1, PM3_Supporting.

The ACADSB c.303+1G>A variant, also known as IVS3+1G>A, has been reported in the homozygous state in two individuals, one individual with a clinical diagnosis of methylbutyryl-CoA dehydrogenase deficiency and the other individual identified by newborn screening (Alfardan J et al., PMID: 20547083). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by eight submitters. This variant is only observed on 77/282,550 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs within the canonical splice donor site, which is predicted to cause skipping of the exon, leading to an out of frame transcript. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31980526, 31589614, 20547083, 33727708)

This sequence change affects a donor splice site in intron 3 of the ACADSB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADSB are known to be pathogenic (PMID: 20547083, 26284228). This variant is present in population databases (rs147936696, gnomAD 0.05%). Disruption of this splice site has been observed in individuals with short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency (PMID: 20547083). This variant is also known as IVS3+1G>A. ClinVar contains an entry for this variant (Variation ID: 203367). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

This patient is a carrier of a heterozygous pathogenic variant in the ACADSB gene associated with 2-methylbutyrylglycinuria. The ACADSB variant (c.303+1G>A) identified in this patient is located in the first intronic position of the donor splice site and, therefore, meets the criteria for a pathogenic variant.