rs118204015
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000018.4(ACADVL):c.1144A>C(p.Lys382Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K382N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000018.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.1144A>C | p.Lys382Gln | missense_variant | 11/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.1144A>C | p.Lys382Gln | missense_variant | 11/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251490Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461786Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727192
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2022 | This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 382 of the ACADVL protein (p.Lys382Gln). This variant is present in population databases (rs118204015, gnomAD 0.006%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACADVL function (PMID: 8554073). 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. ClinVar contains an entry for this variant (Variation ID: 1628). This missense change has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 8554073, 20060901, 29552494, 31497477). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1996 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 04, 2020 | - - |
Likely pathogenic, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Dec 15, 2022 | The NM_000018.4(ACADVL):c.1144A>C (p.Lys382Gln) variant in ACADVL is a missense variant predicted to cause substitution of lysine by glutamine at amino acid 382. The highest population minor allele frequency in gnomAD v 2.1.1 is 0.00005 in East Asian population (one allele), 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 an individual with very long chain acyl CoA dehydrogenase (VLCAD) deficiency, who was compound heterozygous for the variant and a pathogenic variant confirmed in trans by molecular subcloning (PM3, PMID: 8554073). The reported patient with this variant displayed reduced enzyme activities, which is highly specific for the disorder (PP4_Moderate, PMID: 7769092). VLCAD enzyme activity assay in CHO cells showed 19% activity with appropriate controls indicating that this variant impacts protein function (PS3_Supporting, PMID: 8554073). This variant resides within a region, p.382, of ACADVL that is defined as a critical functional domain for FAD binding and salt-bridge interactions by the ClinGen ACADVL VCEP (PM1; PMID: 20060901). The computational predictor REVEL gives a score of 0.95, 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 ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel (PM1, PM3, PP3, PM2_Supporting, PS3_Supporting, PP4_Moderate). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at