rs769894315
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_001698.3(AUH):c.719C>T(p.Ala240Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000582 in 1,614,106 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A240A) has been classified as Likely benign.
Frequency
Consequence
NM_001698.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AUH | NM_001698.3 | c.719C>T | p.Ala240Val | missense_variant | 7/10 | ENST00000375731.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AUH | ENST00000375731.9 | c.719C>T | p.Ala240Val | missense_variant | 7/10 | 1 | NM_001698.3 | P1 | |
AUH | ENST00000303617.5 | c.632C>T | p.Ala211Val | missense_variant | 6/9 | 1 | |||
AUH | ENST00000473695.1 | upstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251382Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135868
GnomAD4 exome AF: 0.0000622 AC: 91AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 727246
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74364
ClinVar
Submissions by phenotype
3-methylglutaconic aciduria type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 15, 2018 | The AUH c.719C>T (p.Ala240Val) variant is a missense variant that has been reported in one study, in which it is found in a compound heterozygous state with a second frameshift variant in an individual with 3-methylglutaconic aciduria type 1 (MGA1). This individual presented with vomiting, insomnia, persistent crying, self-mutilation, and hepatomegaly and responded well to dietary L-carnitine (Ly et al. 2003). The p.Ala240Val variant was absent from 176 control chromosomes but is reported at a 0.000047 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies in E. coli showed that the p.Ala240Val variant reduced enzyme activity to 9% of the wildtype protein (Mack et al. 2006), and overexpressing AUH carrying the p.Ala240Val variant in a human bone cell line significantly lowered the 3-MG-CoA hydratase enzyme activity of AUH (Richman et al. 2014). Based on the evidence, the p.Ala240Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for 3-methylglutaconic aciduria type 1. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | ClinVar contains an entry for this variant (Variation ID: 529797). 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. Experimental studies have shown that this missense change affects AUH function (PMID: 16640564, 24598254). 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 AUH protein function. This missense change has been observed in individual(s) with 3-methylglutaconic aciduria type I (PMID: 12655555, 32778825). This variant is present in population databases (rs769894315, gnomAD 0.005%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 240 of the AUH protein (p.Ala240Val). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 06, 2021 | Expression studies found that A240V reduced 3-methylglutaconyl-coenzyme A hydratase enzyme activity to 9% of wild-type (Mack et al. 2006); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16640564, 9762598, 12655555, 24598254) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at