Submissions for variant NM_000017.4(ACADS):c.988_990delinsTGT (p.Arg330Cys)

dbSNP: rs796051906

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185708	SCV000238629	pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18676165, 16926354, 26055667)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984237	SCV003929036	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-04-26	criteria provided, single submitter	clinical testing	Variant summary: ACADS c.988_990delinsTGT (p.Arg330Cys) results in a non-conservative amino acid change located in the C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. This variant is a multi-nucleotide variant, consisting of c.988C>T (p.R330C) and c.990C>T (p.Arg330=), where the latter synonymous variant is actually the major allele in most subpopulations, and the two variants occur in cis in several carriers (gnomAD). The c.988C>T (p.R330C) variant allele was found at a frequency of 0.00016 in 282298 control chromosomes (gnomAD). The R330C variant has been reported in the literature in multiple individuals affected with Deficiency of Butyryl-CoA Dehydrogenase (van Maldegem_2006, Waisbren_2008, Kiykim_2016, Sadat_2020, Adhikari_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another missense change affecting the same amino acid (c.989G>A/p.R330H) is reported in affected individual(s) (HGMD), supporting the clinical importance of this residue. The following publications have been ascertained in the context of this evaluation (PMID: 16926354, 18676165, 26055667, 31813752, 32778825). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003422082	SCV004118375	likely pathogenic	ACADS-related disorder	2023-06-09	criteria provided, single submitter	clinical testing	The ACADS c.988_990delinsTGT variant is predicted to result in an in-frame deletion and insertion. To our knowledge, this variant has not been reported in the literature. However, a different variant (c.988C>T) leading to the same amino acid substitution has been reported, in the homozygous or compound heterozygous state, in multiple patients with short chain Acyl-CoA dehydrogenase deficiency (SCAD). Multiple reported individuals had biochemical testing consistent with the disease (Sadat et al. 2020. PubMed ID: 31813752, Kiykim et al. 2016. PubMed ID: 26055667, Waisbren et al. 2008. PubMed ID: 18676165, van Maldegem et al. 2006. PubMed ID: 16926354). Another missense variant affecting this nucleotide has also been reported in at least one patient with SCAD deficiency (p.Arg330His, van Maldegem. 2006. PubMed ID: 16926354). This variant was not detected in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
Counsyl	RCV000984237	SCV001132321	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2016-12-21	no assertion criteria provided	clinical testing