19-41422634-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000709.4(BCKDHA):āc.859C>Gā(p.Arg287Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,942 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).
Frequency
Consequence
NM_000709.4 missense
Scores
Clinical Significance
Conservation
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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.859C>G | p.Arg287Gly | missense_variant | 7/9 | ENST00000269980.7 | NP_000700.1 | |
BCKDHA | NM_001164783.2 | c.856C>G | p.Arg286Gly | missense_variant, splice_region_variant | 7/9 | NP_001158255.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BCKDHA | ENST00000269980.7 | c.859C>G | p.Arg287Gly | missense_variant | 7/9 | 1 | NM_000709.4 | ENSP00000269980 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251376Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135880
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461792Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 727206
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 15, 2021 | NM_000709.3(BCKDHA):c.859C>G(R287G) is a missense variant classified as a variant of uncertain significance in the context of maple syrup urine disease type Ia. R287G has been observed in a case with relevant disease (PMID: 32193832). Functional assessments of this variant are not available in the literature. R287G has been observed in population frequency databases (gnomAD: AFR 0.01%). In summary, there is insufficient evidence to classify NM_000709.3(BCKDHA):c.859C>G(R287G) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 19, 2023 | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 287 of the BCKDHA protein (p.Arg287Gly). This variant is present in population databases (rs764247545, gnomAD 0.005%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 32193832). ClinVar contains an entry for this variant (Variation ID: 1334170). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Maple syrup urine disease type 1A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 17, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at