rs140629318
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4_ModeratePM3PP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA275413/MONDO:0008723/021
Frequency
Consequence
NM_000018.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.637G>A | p.Ala213Thr | missense_variant | 8/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.637G>A | p.Ala213Thr | missense_variant | 8/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251298Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135860
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461848Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727228
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74450
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:7
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 07, 2022 | 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. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 21, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Nov 01, 2019 | 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 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 19, 2024 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Apr 15, 2024 | 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). - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2022 | 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 30, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at