Submissions for variant NM_000018.4(ACADVL):c.722A>G (p.Tyr241Cys)

dbSNP: rs575789958

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001069204	SCV001234357	uncertain significance	Very long chain acyl-CoA dehydrogenase deficiency	2019-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with cysteine at codon 241 of the ACADVL protein (p.Tyr241Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs575789958, ExAC 0.009%). This variant has not been reported in the literature in individuals with ACADVL-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001069204	SCV002557439	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with VLCAD deficiency (MIM# 201475). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3) for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated VLCAD domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. It has been reported as VUS by Invitae, likely in this same proband (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1005 - Clinically accredited laboratory assay specific to gene product shows abnormal protein function. Analysis of this proband’s Guthrie card sample has shown an acyl carnitine profile consistent with VLCAD deficiency (VCGS #19M500295). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000018.3(ACADVL):c.552C>A; p.(=)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV003963031	SCV004780400	uncertain significance	ACADVL-related condition	2023-11-14	criteria provided, single submitter	clinical testing	The ACADVL c.722A>G variant is predicted to result in the amino acid substitution p.Tyr241Cys. This variant was previously reported in the heterozygous state as a variant of uncertain significance in a patient with hypoglycemia and rhabdomyolysis (Kiss et al. 2020. PubMed ID: 33351248). Enzymatic testing as well as newborn screening results suggested very long-chain acyl-CoA dehydrogenase deficiency. However, a second variant in ACADVL was not detected (Kiss et al. 2020. PubMed ID: 33351248). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-7125370-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.