rs373534546
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_002225.5(IVD):c.851G>A(p.Arg284Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,934 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R284W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002225.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IVD | NM_002225.5 | c.851G>A | p.Arg284Gln | missense_variant | 8/12 | ENST00000487418.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IVD | ENST00000487418.8 | c.851G>A | p.Arg284Gln | missense_variant | 8/12 | 1 | NM_002225.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152180Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251142Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135758
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461754Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727148
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152180Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74350
ClinVar
Submissions by phenotype
Isovaleryl-CoA dehydrogenase deficiency Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 07, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 15, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 287 of the IVD protein (p.Arg287Gln). This variant is present in population databases (rs373534546, gnomAD 0.008%). This missense change has been observed in individual(s) with a positive newborn screening result for IVD-related disease (PMID: 15486829). ClinVar contains an entry for this variant (Variation ID: 555453). 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. 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 20, 2021 | The c.860G>A (p.R287Q) alteration is located in exon 8 (coding exon 8) of the IVD gene. This alteration results from a G to A substitution at nucleotide position 860, causing the arginine (R) at amino acid position 287 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 03, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R284Q and R255Q; This variant is associated with the following publications: (PMID: 25087612, 32778825, 15486829, 21228398, 24059531) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at