Submissions for variant NM_183050.4(BCKDHB):c.410C>T (p.Ala137Val)

gnomAD frequency: 0.00001  dbSNP: rs776631396

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410485	SCV000486388	likely pathogenic	Maple syrup urine disease	2016-05-26	criteria provided, single submitter	clinical testing
Invitae	RCV000410485	SCV000813246	pathogenic	Maple syrup urine disease	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 137 of the BCKDHB protein (p.Ala137Val). This variant is present in population databases (rs776631396, gnomAD 0.003%). This missense change has been observed in individual(s) with maple syrup urine disease (PMID: 14567968, 16468966, 26830710, 29306928). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 370949). 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 BCKDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects BCKDHB function (PMID: 14567968). For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000410485	SCV000996148	likely pathogenic	Maple syrup urine disease	2018-05-18	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease causing in the Human Gene Mutation Database (HGMD) and is present in ClinVar database as likely pathogenic. Nellis M., et al (PMID: 14567968) showed that it was present as a compound heterozygous change in a patient with maple syrup urine disease (MSUD; OMIM#248600), type 1B. In this report it was shown that the patient had deficient activity of the branched chain a-ketoacid dehydrogenase (BCKD) complex (PMID: 14567968). The c.410C>T (p.Ala137Val) variant is present in the heterozygous state in the gnomAD population database at a very low frequency and thus is presumed to be rare. The c.410C>T (p.Ala137Val) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples showed the mother is heterozygous and the father is negative for this variant. Based on the available evidence, the c.410C>T (p.Ala137Val) variant is classified as likely pathogenic.
Genome-Nilou Lab	RCV000410485	SCV002033145	likely pathogenic	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000410485	SCV002104122	pathogenic	Maple syrup urine disease	2022-02-16	criteria provided, single submitter	clinical testing	Variant summary: BCKDHB c.410C>T (p.Ala137Val) 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 1.2e-05 in 251162 control chromosomes. c.410C>T has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with classic features of Maple Syrup Urine Disease (example, Nellis_2003, Strauss_2006, Stojiljkovic_2016, Zeynalzadeh_2018, Khalifa_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported although individuals homozygous for this variant displayed all the classic biochemical profiles characteristic of Maple Syrup Urine Disease (example, Zeynalzadeh_2018, Khalifa_2020). Five 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000410485	SCV004215955	pathogenic	Maple syrup urine disease	2023-09-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001828375	SCV002077435	pathogenic	Maple syrup urine disease type 1B	2021-02-17	no assertion criteria provided	clinical testing