ClinVar Miner

Submissions for variant NM_183050.4(BCKDHB):c.633+1G>A

gnomAD frequency: 0.00001  dbSNP: rs398124589
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000179048 SCV000231239 pathogenic not provided 2013-08-23 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000811119 SCV000951369 pathogenic Maple syrup urine disease 2024-01-24 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 5 of the BCKDHB gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs398124589, gnomAD 0.006%). Disruption of this splice site has been observed in individual(s) with maple syrup urine disease (MSUD) (PMID: 8312380, 27507644). ClinVar contains an entry for this variant (Variation ID: 96602). Studies have shown that disruption of this splice site results in skipping of exons 5-6 and introduces a premature termination codon (PMID: 8312380). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000179048 SCV001250044 pathogenic not provided 2017-07-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000811119 SCV001983715 pathogenic Maple syrup urine disease 2021-09-08 criteria provided, single submitter clinical testing Variant summary: BCKDHB c.633+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251150 control chromosomes. c.633+1G>A has been reported in the literature in two individuals affected with Maple Syrup Urine Disease, in the homozygous state (Abiri_2017, Abiri_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000811119 SCV002017785 pathogenic Maple syrup urine disease 2019-08-16 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000811119 SCV002033154 pathogenic Maple syrup urine disease 2021-11-07 criteria provided, single submitter clinical testing
National Newborn Screening Laboratory, Hospital Nacional de Niños RCV000811119 SCV002097382 pathogenic Maple syrup urine disease criteria provided, single submitter clinical testing This variant is located within the ±2 bp from a splice site in the BCKDHB gene, where loss of function is a known mechanism of disease. It is present in population databases in low frequency (GnomAD exomes: 0,00001; TopMed: 0,00002). This variant has been published in the literature associated with individuals with MSUD (PMID: 27507644, 31119508). It was found in a compound heterozygous state with a known pathogenic variant in a patient with MSUD phenotype.
Baylor Genetics RCV004566968 SCV004215991 pathogenic Maple syrup urine disease type 1A 2023-12-13 criteria provided, single submitter clinical testing

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