Submissions for variant NM_000018.4(ACADVL):c.1077+15C>T

gnomAD frequency: 0.00041  dbSNP: rs202237278

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV001126555	SCV002576742	likely benign	Very long chain acyl-CoA dehydrogenase deficiency	2022-09-23	reviewed by expert panel	curation	The c.1077+15 C>T variant in ACADVL is an intronic variant which falls downstream of the exon 10 3' splice site. The highest population minor allele frequency in gnomAD v2.1.1 is 0.003767 in the Ashkenazi Jewish population with two homozygotes, which is higher than the ClinGen ACADVL VCEP threshold (>0.0035) for BS1, and therefore meets this criterion (BS1). One individual with this variant did display elevated C14:1 levels on newborn screening, however no values were specified. This same individual was compound heterozygous for this variant and two other variants, though the lack of confirmation in trans disallows this evidence from meeting BP2 (PMID: 27246109; Variants: p.Lys187Glu, c.1678+23 C>T). The results from two in silico splicing predictors (NNSPLICE, SpliceAI) support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as likely benign for VLCAD deficiency in an autosomal recessive manner based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL VCEP: BS1; BP4. Pilot Specifications; Approved on 08/11/2020.
GeneDx	RCV000614488	SCV000719162	likely benign	not specified	2017-09-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV001126555	SCV001285768	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001126555	SCV001365182	benign	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.1077+15C>T (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7222880C>T] variant in ACADVL gene is interpretated to be Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BS1, BS2
Labcorp Genetics (formerly Invitae), Labcorp	RCV001126555	SCV001725279	benign	Very long chain acyl-CoA dehydrogenase deficiency	2024-01-28	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001126555	SCV002088778	likely benign	Very long chain acyl-CoA dehydrogenase deficiency	2020-02-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003953035	SCV004782868	likely benign	ACADVL-related disorder	2020-02-04	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).