ClinVar Miner

Submissions for variant NM_183050.4(BCKDHB):c.832G>A (p.Gly278Ser)

gnomAD frequency: 0.00061  dbSNP: rs386834233
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000762424 SCV000232360 pathogenic not provided 2015-03-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587416 SCV000700012 pathogenic Maple syrup urine disease type 1B 2016-07-08 criteria provided, single submitter clinical testing Variant summary: The BCKDHB c.832G>A (p.Gly278Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). The G278S substitution exhibits a shift in polarity from non-polar to polar, and G278 is located in the Transketolase C-terminal/Pyruvate-ferredoxin oxidoreductase domain II of the 2-oxoisovalerate dehydrogenase subunit beta protein. Functional studies in fibroblasts from compound heterozygous patients show enzyme activity of <10%. This variant was found in 58/120788 control chromosomes at a frequency of 0.0004802, which does not exceed the estimated maximal expected allele frequency of a pathogenic BCKDHB variant (0.0014639). G278S has been reported in numerous MSUD patients in the literature in compound heterozygous state. Furthermore, at least one clinical diagnostic laboratory classified this variant as pathogenic, and the variant is reported as a commonly known pathogenic variant in the literature. Taken together, this variant is classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000762424 SCV000892739 pathogenic not provided 2023-08-01 criteria provided, single submitter clinical testing BCKDHB: PM3:Very Strong, PM2, PP4:Moderate, PP3
Fulgent Genetics, Fulgent Genetics RCV000056009 SCV000894398 pathogenic Maple syrup urine disease 2022-03-28 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000056009 SCV001194015 likely pathogenic Maple syrup urine disease 2019-10-18 criteria provided, single submitter clinical testing NM_183050.2(BCKDHB):c.832G>A(G278S) is classified as likely pathogenic in the context of maple syrup urine disease type Ib and is associated with the intermediate form of this disease. Sources cited for classification include the following: PMID 14567968, 17922217 and 20307994. Classification of NM_183050.2(BCKDHB):c.832G>A(G278S) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Labcorp Genetics (formerly Invitae), Labcorp RCV000056009 SCV001200782 pathogenic Maple syrup urine disease 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 278 of the BCKDHB protein (p.Gly278Ser). This variant is present in population databases (rs386834233, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with BCKDHB-related conditions, some of which present with lab findings that are highly specific for maple syrup urine disease (PMID: 11509994, 14567968, 17922217, 20307994). 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: 65771). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BCKDHB protein function. For these reasons, this variant has been classified as Pathogenic.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital RCV000056009 SCV001519660 pathogenic Maple syrup urine disease 2021-03-16 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000056009 SCV002033158 pathogenic Maple syrup urine disease 2021-11-07 criteria provided, single submitter clinical testing
National Newborn Screening Laboratory, Hospital Nacional de Niños RCV000056009 SCV002097373 pathogenic Maple syrup urine disease criteria provided, single submitter clinical testing This is a missense variant located within exon 7 and generates a change from the aminoacid Glycine to a Serine in position 278. It is present in population databases in low frequency (GnomAD exomes: 0.00055; ExAc: 0.00048). This variant has been published in the literature associated with individuals with MSUD ( PMID: 11509994, PMID: 14517957, PMID: 17922217).
Revvity Omics, Revvity RCV000056009 SCV003821539 likely pathogenic Maple syrup urine disease 2023-02-17 criteria provided, single submitter clinical testing
GeneDx RCV000762424 SCV004034323 pathogenic not provided 2023-09-08 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 23952016, 11509994, 20307994, 17922217, 31980526, 34426522, 33726816, 14517957)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000056009 SCV004046258 pathogenic Maple syrup urine disease criteria provided, single submitter clinical testing This variant has been previously reported in multiple individuals with maple syrup urine disease (MSUD) (PMID: 11509994‚ 14517957‚ 17922217, 14567968, 20307994). The c.832G>A (p.Gly278Ser) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.058% (164/282184). It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.832G>A (p.Gly278Ser) variant is classified as Pathogenic.
Baylor Genetics RCV004566908 SCV004215941 pathogenic Maple syrup urine disease type 1A 2024-03-16 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000587416 SCV005052045 pathogenic Maple syrup urine disease type 1B 2024-02-01 criteria provided, single submitter curation
GeneReviews RCV000056009 SCV000087069 not provided Maple syrup urine disease no assertion provided literature only
PreventionGenetics, part of Exact Sciences RCV004751250 SCV005360367 pathogenic BCKDHB-related disorder 2024-05-03 no assertion criteria provided clinical testing The BCKDHB c.832G>A variant is predicted to result in the amino acid substitution p.Gly278Ser. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with maple syrup urine disease (see for example, Edelmann et al. 2001. PubMed ID: 11509994; Table 2, Flaschker et al. 2007. PubMed ID: 17922217; Puckett et al. 2009. PubMed ID: 20307994). This variant is reported in 0.29% of alleles in individuals of European (Finnish) descent in gnomAD. In vitro experimental studies suggest this variant, in the compound heterozygous state, reduces enzymatic activity (Table 2, Nellis et al. 2003. PubMed ID: 14567968; Table 2, Flaschker et al. 2007. PubMed ID: 17922217). This variant is interpreted as pathogenic.

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