19-41423038-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_000709.4(BCKDHA):c.1036C>T(p.Arg346Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000373 in 1,606,832 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R346H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000709.4 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 |
---|---|---|---|---|---|---|---|
BCKDHA | NM_000709.4 | c.1036C>T | p.Arg346Cys | missense_variant | 8/9 | ENST00000269980.7 | |
BCKDHA | NM_001164783.2 | c.1033C>T | p.Arg345Cys | missense_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCKDHA | ENST00000269980.7 | c.1036C>T | p.Arg346Cys | missense_variant | 8/9 | 1 | NM_000709.4 | P1 | |
BCKDHA | ENST00000457836.6 | c.1045C>T | p.Arg349Cys | missense_variant | 8/9 | 2 | |||
BCKDHA | ENST00000542943.5 | c.949C>T | p.Arg317Cys | missense_variant | 7/7 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000128 AC: 3AN: 235072Hom.: 0 AF XY: 0.0000157 AC XY: 2AN XY: 127160
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1454546Hom.: 0 Cov.: 35 AF XY: 0.00000277 AC XY: 2AN XY: 722840
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152286Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74458
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 346 of the BCKDHA protein (p.Arg346Cys). This variant is present in population databases (rs182923857, gnomAD 0.003%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 24772966). ClinVar contains an entry for this variant (Variation ID: 93335). 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. 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 14, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 25, 2013 | - - |
Maple syrup urine disease type 1A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 18, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at