Submissions for variant NM_000018.4(ACADVL):c.637G>A (p.Ala213Thr)

dbSNP: rs140629318

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ACADVL Variant Curation Expert Panel, ClinGen	RCV000180089	SCV005077910	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-04-15	reviewed by expert panel	curation	The NM_000018.4 c.637G>A (p.Ala213Thr) in ACADVL is a missense variant predicted to cause substitution of alanine by threonine at amino acid 213 (p.Ala213Thr). The highest population minor allele frequency in gnomAD V2.1.1 is 0.00006 in Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant has been detected in homozygous fashion in three consanguinity siblings affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, at least one of whom displayed reduced enzyme levels (17% of wildtype), which is highly specific for VLCAD deficiency (PP4_Moderate, PM3 score = 1.0, PM3, PMID: 12213615). The computational predictor REVEL gives a score of 0.917, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic 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: PM3, PP4_Moderate, PM2_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 9, 2021).
Eurofins Ntd Llc (ga)	RCV000723371	SCV000232457	pathogenic	not provided	2014-09-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000180089	SCV000823384	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 213 of the ACADVL protein (p.Ala213Thr). This variant is present in population databases (rs140629318, gnomAD 0.006%). This missense change has been observed in individual(s) with very long chain acyl-CoA dehydrogenase deficiency (PMID: 12213615, 24801231). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 198683). 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 with a positive predictive value of 95%. This variant disrupts the p.Ala213 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in individuals with ACADVL-related conditions (PMID: 10077518), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	RCV000180089	SCV001364896	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2019-11-01	criteria provided, single submitter	clinical testing	The NM_000018.3:c.637G>A (NP_000009.1:p.Ala213Thr) [GRCH38: NC_000017.11:g.7221966G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID: 12213615. This variant meets the following evidence codes reported in the ACMG guidelines: PS1, PS3
Revvity Omics, Revvity	RCV000180089	SCV002021264	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-10-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000180089	SCV002048375	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2022-07-07	criteria provided, single submitter	clinical testing	The ACADVL c.637G>A; p.Ala213Thr variant (rs140629318), also reported as p.Ala173Thr, is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, including three homozygous siblings (Straussberg 2002, Zhang 2014). This variant is also reported in ClinVar (Variation ID: 198683). This variant is found in the general population with an overall allele frequency of 0.002% (5/251298 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (c.637G>C; p.Ala213Pro) has been reported in a homozygous individual with VLCAD deficiency and is considered disease-causing (Mathur 1999). The alanine at codon 213 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.917). Based on the above information, the variant is classified as likely pathogenic. References: Mathur A et al. Molecular heterogeneity in very-long-chain acyl-CoA dehydrogenase deficiency causing pediatric cardiomyopathy and sudden death. Circulation. 1999 Mar 16;99(10):1337-43. PMID: 10077518. Straussberg R et al. A novel mutation of late-onset very-long-chain acyl-CoA dehydrogenase deficiency. Pediatr Neurol. 2002 Aug;27(2):136-7. PMID: 12213615. Zhang RN et al. Clinical features and mutations in seven Chinese patients with very long chain acyl-CoA dehydrogenase deficiency. World J Pediatr. 2014 May;10(2):119-25. PMID: 24801231.
Ambry Genetics	RCV002515289	SCV003549338	likely pathogenic	Inborn genetic diseases	2022-01-19	criteria provided, single submitter	clinical testing	The c.637G>A (p.A213T) alteration is located in exon 8 (coding exon 8) of the ACADVL gene. This alteration results from a G to A substitution at nucleotide position 637, causing the alanine (A) at amino acid position 213 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (5/251298) total alleles studied. The highest observed frequency was 0.01% (2/34576) of Latino alleles. This variant has been reported in the homozygous and compound heterozygous states in patients with very long chain acyl-CoA dehydrogenase deficiency (Straussberg, 2002; Zhang, 2014; Gillingham, 2017). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV000180089	SCV004214162	pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2024-02-19	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000180089	SCV001455125	likely pathogenic	Very long chain acyl-CoA dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing