Submissions for variant NM_000018.4(ACADVL):c.623-8C>T

gnomAD frequency: 0.00919  dbSNP: rs144996066

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000322156	SCV002576756	benign	Very long chain acyl-CoA dehydrogenase deficiency	2022-03-08	reviewed by expert panel	curation	The c.623-8C>T variant in ACADVL is an intronic variant which occurs in the polypyrimidine tract of intron 7. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0289 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The results from 2 in silico splicing predictors (SpliceAI, NNSplice) support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4 (VCEP specifications v2.0, approved on 09/16/2021).
Eurofins Ntd Llc (ga)	RCV000152736	SCV000202123	benign	not specified	2014-02-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000322156	SCV000406313	benign	Very long chain acyl-CoA dehydrogenase deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000152736	SCV000511942	benign	not specified	2015-12-03	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000322156	SCV000602372	benign	Very long chain acyl-CoA dehydrogenase deficiency	2023-01-06	criteria provided, single submitter	clinical testing
Invitae	RCV000322156	SCV000654957	benign	Very long chain acyl-CoA dehydrogenase deficiency	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152736	SCV001362325	benign	not specified	2019-11-05	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.623-8C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0028 in 282452 control chromosomes, predominantly at a frequency of 0.029 within the African or African-American subpopulation in the gnomAD database, including 14 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACADVL causing Very Long Chain Acyl-CoA Dehydrogenase Deficiency phenotype (0.0029), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.623-8C>T in individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (3 classifying the variant as benign, while 1 reporting it as a VUS). Based on the evidence outlined above, the variant was classified as benign.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000322156	SCV001365179	benign	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.623-8C>T (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7221944C>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
Fulgent Genetics, Fulgent Genetics	RCV000322156	SCV002794621	likely benign	Very long chain acyl-CoA dehydrogenase deficiency	2021-10-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000322156	SCV001455123	benign	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing