rs137852872
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_000709.4(BCKDHA):c.1226T>G(p.Phe409Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. F409L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000709.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BCKDHA | NM_000709.4 | c.1226T>G | p.Phe409Cys | missense_variant | 9/9 | ENST00000269980.7 | |
BCKDHA | NM_001164783.2 | c.1223T>G | p.Phe408Cys | missense_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BCKDHA | ENST00000269980.7 | c.1226T>G | p.Phe409Cys | missense_variant | 9/9 | 1 | NM_000709.4 | P1 | |
BCKDHA | ENST00000457836.6 | c.1235T>G | p.Phe412Cys | missense_variant | 9/9 | 2 | |||
BCKDHA | ENST00000544905.1 | c.62-6T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Maple syrup urine disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2023 | ClinVar contains an entry for this variant (Variation ID: 2378). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 409 of the BCKDHA protein (p.Phe409Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MSUD (PMID: 7883996; Invitae). This variant is also known as F364C. 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. Experimental studies have shown that this missense change affects BCKDHA function (PMID: 7883996). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 22, 1998 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 15, 2022 | Variant summary: BCKDHA c.1226T>G (p.Phe409Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249270 control chromosomes (gnomAD). c.1226T>G (also known as F364C) has been reported in the literature in at-least one homozygous individual affected with Maple Syrup Urine Disease (Chuang_1995). Experimental evidence evaluating protein function have demonstrated that this variant effect results in <10% of normal activity (e.g. Chuang_1995, Wynn_1998). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at