rs145901144
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000709.4(BCKDHA):c.889C>T(p.Arg297Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000143 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000709.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BCKDHA | NM_000709.4 | c.889C>T | p.Arg297Cys | missense_variant | 7/9 | ENST00000269980.7 | NP_000700.1 | |
BCKDHA | NM_001164783.2 | c.886C>T | p.Arg296Cys | missense_variant | 7/9 | NP_001158255.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BCKDHA | ENST00000269980.7 | c.889C>T | p.Arg297Cys | missense_variant | 7/9 | 1 | NM_000709.4 | ENSP00000269980.2 | ||
ENSG00000255730 | ENST00000540732.3 | c.991C>T | p.Arg331Cys | missense_variant | 8/10 | 2 | ENSP00000443246.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251450Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135908
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461850Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727228
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 05, 2023 | 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 BCKDHA protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg297 amino acid residue in BCKDHA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10745006, 17922217, 29306928). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 555477). This missense change has been observed in individuals with maple syrup urine disease (PMID: 16786533, 28830848). This variant is present in population databases (rs145901144, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 297 of the BCKDHA protein (p.Arg297Cys). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 06, 2017 | - - |
Maple syrup urine disease type 1A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 05, 2023 | Variant summary: BCKDHA c.889C>T (p.Arg297Cys) results in a non-conservative amino acid change located in the Dehydrogenase, E1 component (IPR001017) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251450 control chromosomes (gnomAD). c.889C>T has been reported in the literature in individuals affected with Maple Syrup Urine Disease (examples: Rodriguez-Pombo_2006 and Cheng_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28830848, 16786533). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at