Submissions for variant NM_183050.4(BCKDHB):c.93_103del (p.Ala32fs)

dbSNP: rs398124601

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000173586	SCV000224710	pathogenic	not provided	2016-03-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780961	SCV000918644	pathogenic	Maple syrup urine disease type 1B	2018-12-13	criteria provided, single submitter	clinical testing	Variant summary: BCKDHB c.93_103del11 (p.Ala32PhefsX48) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 234612 control chromosomes (gnomAD). c.93_103del11 has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease (Tabbouche_2014, Rodriguez-Pombo_2006, Parrella_1994, Nobukuni_1991). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that the variant caused a severe decrease in BCKDH enzyme activity and also, resulted in absence of E1 beta subunit of BCKDH while the E1 alpha subunit of BCKDH was markedly reduced (Nobukuni_1991). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001390112	SCV001591736	pathogenic	Maple syrup urine disease	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala32Phefs*48) in the BCKDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHB are known to be pathogenic (PMID: 16786533, 22593002). This variant is present in population databases (rs751389206, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 2022752, 31112740). It has also been observed to segregate with disease in related individuals. This variant is also known as c.92_102del11. ClinVar contains an entry for this variant (Variation ID: 96618). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001390112	SCV002017763	pathogenic	Maple syrup urine disease	2021-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001390112	SCV002033137	pathogenic	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004566972	SCV004215976	pathogenic	Maple syrup urine disease type 1A	2023-12-13	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001390112	SCV004847419	pathogenic	Maple syrup urine disease	2024-01-29	criteria provided, single submitter	clinical testing	The p.Ala32PhefsX48 variant in BCKDHB has been reported in the homozygous and compound heterozygous state in at least 4 individuals (2 homozygotes, 2 compound heterozygote with at least one disease causing allele in BCKDHB) with maple syrup urine disease (MSUD) and segregated with disease in 2 affected relatives from 1 family (Nobukuni 1991 PMID: 2022752, Rodriguez-Pombo 2006 PMID: PMID: 16786533, Tabbouche 2014 PMID: 27896100, Yang 2019 PMID: 31112740). It at least 2 individuals, BCKDH enzyme activity was severely reduced (Nobukuni 1991 PMID: 2022752, Rodriguez-Pombo 2006 PMID: 16786533). The variant was also detected in the heterozygous state in 2 families with MSUD where a second variant was not identified (Parella 1994 PMID: 7707687). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 96618) and has also been identified in 0.002% (1/41438) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is a deletion of 11 base pairs and is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at amino acid 32 and leads to a premature termination codon 48 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the BCKDHB gene is an established disease mechanism in autosomal recessive MSUD. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MSUD. ACMG/AMP Criteria applied: PVS1, PM3_Moderate, PP1, PM2_Supporting, PP4.
OMIM	RCV000780961	SCV000032949	pathogenic	Maple syrup urine disease type 1B	1991-05-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000780961	SCV001455530	pathogenic	Maple syrup urine disease type 1B	2020-09-16	no assertion criteria provided	clinical testing