rs1555404933
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_002225.5(IVD):c.881T>C(p.Leu294Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L294F) has been classified as Uncertain significance.
Frequency
Consequence
NM_002225.5 missense, splice_region
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 |
---|---|---|---|---|---|---|---|
IVD | NM_002225.5 | c.881T>C | p.Leu294Pro | missense_variant, splice_region_variant | 9/12 | ENST00000487418.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IVD | ENST00000487418.8 | c.881T>C | p.Leu294Pro | missense_variant, splice_region_variant | 9/12 | 1 | NM_002225.5 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Isovaleryl-CoA dehydrogenase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 06, 2020 | 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. 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. This variant has not been reported in the literature in individuals with IVD-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 297 of the IVD protein (p.Leu297Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at