ClinVar Genomic variation as it relates to human health

The BCKDHB c.548G>C (p.Arg183Pro) missense variant has been identified in a total of seven individuals diagnosed with maple syrup urine disease, including five who were homozygous for the variant and two who were compound heterozygous (Edelmann et al. 2001; Carecchio et al. 2011). All of these individuals were of Ashkenazi Jewish descent. Edelmann et al. (2001) also identified the variant in a heterozygous state in 9/1014 Ashkenazi Jewish individuals from the New York metro area, indicating a carrier frequency of 1/113 in this population. The p.Arg183Pro variant is reported at a frequency of 0.00047 in the European-American population of the Exome Sequencing Project. The Arg183 residue is conserved. Based on the evidence, the p.Arg183Pro variant is classified as pathogenic for maple syrup urine disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

DNA sequence analysis of the BCKDHB gene demonstrated a sequence change, c.548G>C, in exon 5 that results in an amino acid change, p.Arg183Pro. This sequence change has been described in the EXAC database with a low population frequency of 0.02% (dbSNP rs79761867). This pathogenic sequence change has previously been described in patients with maple syrup urine disease (MSUD). The p.Arg183Pro change affects a highly conserved amino acid residue located in a domain of the BCKDHB protein that is known to be functional. The p.Arg183Pro substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This variant is a reported to be a common pathogenic variant in the Ashkenazi Jewish population (PMID: 11509994). Other variants involving this codon have been reported in association with MSUD [OMIM#.248600].

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: 26257134, 28197878, 22593002, 21844576, 11509994, 27175728, 25087612, 27403441, 24268812, 19456321, 23757202, 32151765, 31980395, 31980526, 32778825, 21484869)

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 183 of the BCKDHB protein (p.Arg183Pro). This variant is present in population databases (rs79761867, gnomAD 0.5%). This missense change has been observed in individuals with maple syrup urine disease (PMID: 11509994, 26257134). ClinVar contains an entry for this variant (Variation ID: 11937). 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%. This variant disrupts the p.Arg183 amino acid residue in BCKDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22593002). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Variant summary: BCKDHB c.548G>C affects a conserved nucleotide, resulting in amino acid change from Arg to Pro. 5/5 in-silico tools predict damaging outcome for this variant. This variant is found in 33/123400 control chromosomes at a frequency of 0.0002674, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0014639). The variant has been cited in multiple MSUD patients in homozygous and compound heterozygous state. In addition, at least 1 clinical laboratory classified this variant as pathogenic. Taken together, this is a disease variant and was classified as pathogenic.

NM_183050.2(BCKDHB):c.548G>C(R183P) is classified as likely pathogenic in the context of maple syrup urine disease type Ib and is associated with the classic form of the disease. Sources cited for classification include the following: PMID 11509994, 25255367 and 11448970. Classification of NM_183050.2(BCKDHB):c.548G>C(R183P) 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

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with maple syrup urine disease, type Ib (MIM#248600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (62 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (8 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated transketolase pyrimidine binding domain (Decipher). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These alternative missense variants p.(Arg183Trp), p.(Arg183Gln) have been previously reported as likely pathogenic, and observed in individuals with maple syrup urine disease (MSUD) (ClinVar, PMID: 28197878). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and likely pathogenic, and has been reported in mostly homozygous Ashkenazi Jewish individuals with classic MSUD (ClinVar, PMID: 11509994). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The c.548G>C (p.R183P) alteration is located in exon 5 (coding exon 5) of the BCKDHB gene. This alteration results from a G to C substitution at nucleotide position 548, causing the arginine (R) at amino acid position 183 to be replaced by a proline (P). Based on data from the Genome Aggregation Database (gnomAD) database, the BCKDHB c.548G>C alteration was observed in 0.02% (62/282734) of total alleles studied, with a frequency of 0.53% (55/10368) in the Ashkenazi Jewish subpopulation. This alteration has been reported in the homozygous and compound heterozygous states in patients with maple syrup urine disease and is a common founder mutation in the Ashkenazi Jewish population (Edelmann, 2001; Gupta, 2015). This amino acid position is highly conserved in available vertebrate species. Functional studies demonstrate that this alteration affects protein activity and stability in a temperature-dependent manner (Wynn, 2001). The p.R183P alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

NM_183050.2:c.548G>C in the BCKDHB gene has an allele frequency of 0.005 in Ashkenazi Jewish subpopulation in the gnomAD database. The BCKDHB c.548G>C (p.Arg183Pro) missense variant has been identified in a total of seven individuals diagnosed with maple syrup urine disease, including five who were homozygous for the variant and two who were compound heterozygous (PMID: 11509994; 21484869). It is a founder mutation in the Ashkenazi Jewish Population. In-silico tools predict a damaging effect of the variant on protein function (PMID: 11509994). Pathogenic computational verdict because 11 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PM3_Strong; PP4; PP3.

Variant interpretted as Likely pathogenic and reported on 11-16-2013 by Lab or GTR ID 320494. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.