ClinVar Miner

Submissions for variant NM_183050.4(BCKDHB):c.1006G>A (p.Gly336Ser) (rs398124560)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000082719 SCV000114763 likely pathogenic not provided 2017-12-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587204 SCV000700009 likely pathogenic Maple syrup urine disease type 1B 2017-08-09 criteria provided, single submitter clinical testing Variant summary: The BCKDHB c.1006G>A (p.Gly336Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121244 control chromosomes. A recent report of a Saudi Arabian cohort with a high level of consanguinity describes three classically affected patients (biochemical diagnosis confirmed) from three different families to be homozygous for the variant, while the variant was absent in 200 ethnically matched controls (Imtiaz_2017). Based on modeling studies, the authors predicted this variant to lead to desabalization of the protein. One clinical diagnostic laboratory classified this variant as uncertain significance, last evaluated in 2013. Taken together, this variant is classified as likely pathogenic based on all patients reported from a single publication without validation.
Counsyl RCV000674620 SCV000799989 likely pathogenic Maple syrup urine disease 2018-05-16 criteria provided, single submitter clinical testing
Invitae RCV000674620 SCV000941010 likely pathogenic Maple syrup urine disease 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 336 of the BCKDHB protein (p.Gly336Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with maple syrup urine disease (PMID: 28417071, 28830848). ClinVar contains an entry for this variant (Variation ID: 96562). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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