Submissions for variant NM_000017.4(ACADS):c.1108A>G (p.Met370Val)

gnomAD frequency: 0.00009  dbSNP: rs566325901

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185696	SCV000238617	likely benign	not provided	2021-06-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27535533, 18523805)
Illumina Laboratory Services, Illumina	RCV000301353	SCV000376688	uncertain significance	Deficiency of butyryl-CoA dehydrogenase	2017-04-27	criteria provided, single submitter	clinical testing	The ACADS c.1108A>G (p.Met370Val) missense variant has been reported in one study in which it is found in a compound heterozygous state in three patients with short-chain acyl-coA dehydrogenase (SCAD) deficiency (Pedersen et al. 2008). The p.Met370Val variant was absent from 100 control alleles but is reported at a frequency of 0.0143 in the South Asian population of the Exome Aggregation Consortium. Functional studies showed that the variant resulted in temperature sensitive decreased tetramer formation and an increased aggregation tendency compared to wild type (Pedersen et al. 2008). The evidence for this variant is limited. The p.Met370Val variant is therefore classified as likely pathogenic for short-chain acyl-coA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001258242	SCV001435155	likely benign	Type 2 diabetes mellitus		criteria provided, single submitter	research	The heterozygous p.Met370Val variant in ACADS has been identified in 3 individuals with Acyl-CoA-dehydrogenase deficiency (PMID: 18523805), but has also been identified in >1% of South Asian chromosomes and 6 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Met370Val variant may slightly impact protein function (PMID: 18523805). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for Acyl-CoA-dehydrogenase deficiency.
Genome-Nilou Lab	RCV000301353	SCV002033259	likely benign	Deficiency of butyryl-CoA dehydrogenase	2021-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV000301353	SCV002486913	benign	Deficiency of butyryl-CoA dehydrogenase	2023-12-11	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000301353	SCV002761848	uncertain significance	Deficiency of butyryl-CoA dehydrogenase	2022-04-19	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000301353	SCV004698129	likely risk allele	Deficiency of butyryl-CoA dehydrogenase		criteria provided, single submitter	research	Potent mutations in ACADS gene can lead to short chain acyl coA dehydrogenase deficiency, which is presents in pediatric age group as one of the fatty acid oxidation disorder. Usually asymptomatic in adults or can present with musculoskeletal symptoms. Carnitine and Riboflavin supplementation have been recommended in some stuides. However, more evidence required to ascertain the role of this variant rs566325901 in short chain acyl coA dehydrogenase deficiency.