rs371518124
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_183050.4(BCKDHB):c.509G>A(p.Arg170His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,930 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R170P) has been classified as Uncertain significance.
Frequency
Consequence
NM_183050.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCKDHB | NM_183050.4 | c.509G>A | p.Arg170His | missense_variant | 5/10 | ENST00000320393.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCKDHB | ENST00000320393.9 | c.509G>A | p.Arg170His | missense_variant | 5/10 | 1 | NM_183050.4 | P1 | |
BCKDHB | ENST00000356489.9 | c.509G>A | p.Arg170His | missense_variant | 5/11 | 1 | P1 | ||
BCKDHB | ENST00000369760.8 | c.509G>A | p.Arg170His | missense_variant | 5/6 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 152076Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251426Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135888
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461854Hom.: 0 Cov.: 34 AF XY: 0.0000385 AC XY: 28AN XY: 727232
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74288
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:3Uncertain:1
Uncertain significance, flagged submission | clinical testing | Counsyl | May 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 14, 2021 | Variant summary: BCKDHB c.509G>A (p.Arg170His) results in a non-conservative amino acid change located in the Transketolase-like, pyrimidine-binding domain (IPR005475) 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 3.2e-05 in 251526 control chromosomes (gnomAD and publication data). c.509G>A has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease, including two homozygotes (Wang_2012, Miryounesi_2015, Strauss_2020, OReilly_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 170 of the BCKDHB protein (p.Arg170His). This variant is present in population databases (rs371518124, gnomAD 0.01%). This missense change has been observed in individual(s) with BCKDHB-related conditions (PMID: 22326532; Invitae). ClinVar contains an entry for this variant (Variation ID: 96591). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg170 amino acid residue in BCKDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25381949, 26453840, 27682710). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 11, 2023 | 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; This variant is associated with the following publications: (PMID: 25381949, 34883003, 22326532, 33300147, 31980395) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 06, 2015 | - - |
Maple syrup urine disease type 1A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at