Submissions for variant NM_000709.4(BCKDHA):c.117del (p.Arg40fs)

dbSNP: rs398123489

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079223	SCV000227166	pathogenic	not provided	2013-08-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000079223	SCV000566136	pathogenic	not provided	2021-11-22	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26232051, 31980395, 16786533, 25333063, 31589614, 18378174)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000175640	SCV001235720	pathogenic	Maple syrup urine disease	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg40Glyfs*23) in the BCKDHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BCKDHA are known to be pathogenic (PMID: 16786533, 22593002). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with maple syrup urine disease (PMID: 16786533, 25333063). ClinVar contains an entry for this variant (Variation ID: 93342). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193901	SCV001363067	pathogenic	Maple syrup urine disease type 1A	2020-10-18	criteria provided, single submitter	clinical testing	Variant summary: BCKDHA c.117delC (p.Arg40GlyfsX23) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 250946 control chromosomes. c.117delC has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease Type 1A (example, Couce_2015, Fernandez_Guerra_2014, Quental_2008, Strauss_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Fernandez_Guerra_2014). The most pronounced variant effect resulted in a loss of detectable levels of protein subunit E1alpha that is encoded by BCKDHA in human dermal fibroblasts from classic MSUD patients. Three 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.
Genome-Nilou Lab	RCV000175640	SCV001810298	pathogenic	Maple syrup urine disease	2021-07-22	criteria provided, single submitter	clinical testing
National Newborn Screening Laboratory, Hospital Nacional de Niños	RCV000175640	SCV002097372	pathogenic	Maple syrup urine disease		criteria provided, single submitter	clinical testing	This is a frame-shift variant in the BCKDHA gene, where loss of function is a known mechanism of disease. This variant results in a truncated protein by creating a premature stop codon. It has been published in the literature associated with individuals with MSUD (PMID: 16786533, PMID: 25333063, PMID: 26232051).
Fulgent Genetics, Fulgent Genetics	RCV000175640	SCV002778126	pathogenic	Maple syrup urine disease	2022-04-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000175640	SCV003813662	pathogenic	Maple syrup urine disease	2022-07-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001193901	SCV004215875	pathogenic	Maple syrup urine disease type 1A	2024-03-06	criteria provided, single submitter	clinical testing
OMIM	RCV000175640	SCV000022640	pathogenic	Maple syrup urine disease	2009-05-01	no assertion criteria provided	literature only
Counsyl	RCV000175640	SCV000486658	pathogenic	Maple syrup urine disease	2016-11-03	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001193901	SCV001461584	pathogenic	Maple syrup urine disease type 1A	2020-09-16	no assertion criteria provided	clinical testing