Submissions for variant NM_000016.6(ACADM):c.599+1G>A

gnomAD frequency: 0.00001  dbSNP: rs866388216

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000211443	SCV000268443	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2015-02-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000211443	SCV000485329	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2015-11-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000211443	SCV002230736	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-02-25	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 of the ACADM 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 ACADM are known to be pathogenic (PMID: 16121256, 20434380). This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with medium chain acyl-CoA dehydrogenase (MCAD) deficiency (PMID: 20434380). ClinVar contains an entry for this variant (Variation ID: 226060). 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.
Fulgent Genetics, Fulgent Genetics	RCV000211443	SCV002808629	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2022-02-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000211443	SCV004216252	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-10-12	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000211443	SCV005398992	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deficiency of medium chain acyl-CoA dehydrogenase (MCAD) (MIM#201450). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical presentation varies from asymptomatic to fulminant course (OMIM). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 2 heterozygotes, 0 homozygotes). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v3) at a frequency of 0.000006570 (1 heterozygote, 0 homozygotes). (SB) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by multiple clinical laboratories in ClinVar. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc.	RCV000211443	SCV001461465	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917863	SCV004731922	likely pathogenic	ACADM-related disorder	2024-02-02	no assertion criteria provided	clinical testing	The ACADM c.599+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant was not reported in patients with MCAD deficiency. However, a different variant affecting this donor site has been reported, along with the recurrent c.985A>G pathogenic variant, in a patient with biochemical markers consistent with MCAD deficiency (c.599+3A>G; Navarrete et al. 2019. PubMed ID: 30626930). The c.599+1G>A variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-76205796-G-A). Variants that disrupt the consensus splice donor site in ACADM are expected to be pathogenic. This variant is interpreted as likely pathogenic.