Submissions for variant NM_000018.4(ACADVL):c.577G>C (p.Gly193Arg)

gnomAD frequency: 0.00001  dbSNP: rs763630981

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV001200732	SCV002769752	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2022-12-14	reviewed by expert panel	curation	The c.577G>C variant in ACADVL is a missense variant predicted to cause substitution of glycine by arginine at amino acid 193 (p.Gly193Arg). This variant has been described in several reportedly affected individuals, and at least one individual displayed VLCAD enzyme levels <20% of controls which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Moderate; PMIDs: 25834949, 25737446). The variant has been described not confirmed in trans to distinct uncertain variants and has also been described in the homozygous state in an individual who did not meet PP4 criteria and was therefore unable to be counted toward PM3 data (PMIDs: 25834949, 25737446, 17999356, 16950999, 25737446, 24305961,16435213, 25834949). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021).
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV001200732	SCV001364893	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.577G>C (NP_000009.1:p.Gly193Arg) [GRCH38: NC_000017.11:g.7221637G>C] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 16435213; 25834949. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Baylor Genetics	RCV001200732	SCV004211932	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-03-08	criteria provided, single submitter	clinical testing
Invitae	RCV001200732	SCV004297746	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 193 of the ACADVL protein (p.Gly193Arg). This variant is present in population databases (rs763630981, gnomAD 0.003%). This missense change has been observed in individual(s) with VLCAD deficiency (PMID: 25834949). ClinVar contains an entry for this variant (Variation ID: 932788). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.