Submissions for variant NM_183050.4(BCKDHB):c.509G>C (p.Arg170Pro)

dbSNP: rs371518124

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082750	SCV000114794	uncertain significance	not provided	2012-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631889	SCV000752990	uncertain significance	Maple syrup urine disease	2022-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 170 of the BCKDHB protein (p.Arg170Pro). This variant is present in population databases (rs371518124, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BCKDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 96592). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant disrupts the p.Arg170 amino acid residue in BCKDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22326532; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000631889	SCV002033132	uncertain significance	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002513855	SCV003587403	likely pathogenic	Inborn genetic diseases	2022-01-13	criteria provided, single submitter	clinical testing	The c.509G>C (p.R170P) 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 509, causing the arginine (R) at amino acid position 170 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (5/251426) total alleles studied. The highest observed frequency was 0.01% (5/34592) of Latino alleles. This variant was identified as homozygous in an individual affected with Maple syrup urine disease (Clinvar database). In addition, multiple different variants at this position have been described in patients with Maple syrup urine disease including p.R170H, p.R170C, and p.R170G (Li, 2018; Abiri, 2019; Strauss, 2020; O'Reilly, 2021). Based on internal structural analysis, the p.R170P variant was determined to be more destabilizing than these previously reported variants (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004751259	SCV005365816	likely pathogenic	BCKDHB-related disorder	2024-05-03	no assertion criteria provided	clinical testing	The BCKDHB c.509G>C variant is predicted to result in the amino acid substitution p.Arg170Pro. To our knowledge, this variant has not been reported in the literature. However, alternate nucleotide substitutions affecting the same amino acid (p.Arg170Cys, p.Arg170His, and p.Arg170Gly) have been reported in the homozygous and compound heterozygous states in multiple individuals with maple syrup urine disease (see for example, Miryounesi et al. 2015. PubMed ID: 25381949; Table 3, OReilly et al. 2020. PubMed ID: 33300147; Table S1, Strauss et al. 2020. PubMed ID: 31980395). The p.Arg170 amino acid has been highly evolutionarily conserved (Alamut Visual v2.11). In silico analysis suggested that the p.Arg170 residue is in close proximity to the K+ binding site in the branched-chain alpha-ketoacid dehydrogenase (BCKD) enzyme complex, and that substitutions of this amino acid may cause unstable dimer assembly and an unstable K+ ion binding loop (Miryounesi et al. 2015. PubMed ID: 25381949). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic.