Submissions for variant NM_183050.4(BCKDHB):c.1016C>T (p.Ser339Leu)

gnomAD frequency: 0.00002  dbSNP: rs398124561

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180715	SCV000233195	pathogenic	not provided	2015-04-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001052144	SCV001216341	pathogenic	Maple syrup urine disease	2024-02-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 339 of the BCKDHB protein (p.Ser339Leu). 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 missense change has been observed in individual(s) with BCKDHB-related conditions (PMID: 11448970, 22593002, 30228974; Invitae). This variant is also known as p.Ser289Leu. ClinVar contains an entry for this variant (Variation ID: 96563). 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 not expected to disrupt BCKDHB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects BCKDHB function (PMID: 11448970). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV001052144	SCV002033165	likely pathogenic	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001052144	SCV003809125	pathogenic	Maple syrup urine disease	2021-11-29	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV001052144	SCV003841236	likely pathogenic	Maple syrup urine disease		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.1016C>T in Exon 9 of the BCKDHB gene that results in the amino acid substitution p.Ser339Leu was identified. The observed variant has a minor allele frequency of 0.00003 in and genomes and is novel in gnomAD exomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID: 96563]. This variant has previously been reported for maple syrup urine disease by Ali, Ernie Zuraida, and Lock-Hock Ngu., 2018. Experimental studies have shown that this missense change affects BCKDHB function by Wynn, R. Max, et al., 2001. For these reasons this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001052144	SCV003844461	pathogenic	Maple syrup urine disease	2023-02-08	criteria provided, single submitter	clinical testing	Variant summary: BCKDHB c.1016C>T (p.Ser339Leu) results in a non-conservative amino acid change located in the Transketolase, C-terminal domain (IPR033248) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250844 control chromosomes (gnomAD). c.1016C>T has been reported in the literature in multiple individuals affected with Maple Syrup Urine Disease (e.g. Wynn_2001, Gorzelany_2009, Bashyam_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated complete absence of activity in patient derived fibroblasts, and in a bacterial expression system (Wynn_2001). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, partly without evidence for independent evaluation, and classified the variant as pathogenic (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV004566959	SCV004215959	pathogenic	Maple syrup urine disease type 1A	2024-03-05	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV004566958	SCV005052044	pathogenic	Maple syrup urine disease type 1B	2024-02-01	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV004566958	SCV005674015	likely pathogenic	Maple syrup urine disease type 1B	2024-03-26	criteria provided, single submitter	clinical testing