Submissions for variant NM_000018.4(ACADVL):c.439C>T (p.Pro147Ser)

dbSNP: rs1032857886

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000673732	SCV002576738	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-09-22	reviewed by expert panel	curation	The c.439C>T (p.Pro147Ser) variant in ACADVL is a missense in exon 6. This variant has been reported once in the literature in a proband with very-long chain acyl-CoA dehydrogenase deficiency, and elevated C14:1 in NBS (PP4, PMID27209629). This variant is absent from population databases gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.88, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). However, there is insufficient experimental or case data identified in the literature for this variant and is therefore classified as a VUS. (ACADVL-specific ACMG/AMP criteria applied: PP4; PM2_supporting; PP3).
Counsyl	RCV000673732	SCV000798969	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2018-04-04	criteria provided, single submitter	clinical testing
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000673732	SCV001365017	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.439C>T (NP_000009.1:p.Pro147Ser) [GRCH38: NC_000017.11:g.7221020C>T] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PM1, PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000673732	SCV002186086	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2021-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline with serine at codon 147 of the ACADVL protein (p.Pro147Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of very long chain acyl-CoA dehydrogenase deficiency (PMID: 27209629). ClinVar contains an entry for this variant (Variation ID: 557575). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526007	SCV005040193	uncertain significance	not specified	2024-03-06	criteria provided, single submitter	clinical testing	Variant summary: ACADVL c.439C>T (p.Pro147Ser) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251368 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.439C>T has been reported in the literature in at-least one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (example: Pena_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27209629). ClinVar contains an entry for this variant (Variation ID: 557575). Based on the evidence outlined above, the variant was classified as uncertain significance.