Submissions for variant NM_183050.4(BCKDHB):c.995C>T (p.Pro332Leu)

dbSNP: rs1554205541

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498242	SCV000589733	likely pathogenic	not provided	2016-01-25	criteria provided, single submitter	clinical testing	The P332L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P332L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P332L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000530607	SCV000627823	pathogenic	Maple syrup urine disease	2023-04-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 432059). This missense change has been observed in individual(s) with maple syrup urine disease (MSUD) (Invitae; http//d-nb.info/1009923471/34). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 332 of the BCKDHB protein (p.Pro332Leu).
Counsyl	RCV000530607	SCV000799489	uncertain significance	Maple syrup urine disease	2018-04-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000498242	SCV000892740	uncertain significance	not provided	2018-09-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000530607	SCV002033124	likely pathogenic	Maple syrup urine disease	2021-11-07	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000530607	SCV003807892	likely pathogenic	Maple syrup urine disease	2022-11-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated, PM3 moderated, PP3 supporting, PP4
PreventionGenetics, part of Exact Sciences	RCV003419842	SCV004117920	uncertain significance	BCKDHB-related condition	2023-07-13	criteria provided, single submitter	clinical testing	The BCKDHB c.995C>T variant is predicted to result in the amino acid substitution p.Pro332Leu. This variant has been reported in the homozygous state in an individual with Maple syrup urine disease (Table 2, Nair et al. 2018. PubMed ID: 30293248; Table 3, Khalifa et al. 2020. PubMed ID: 32812330). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. While we suspect that this variant is pathogenic, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000530607	SCV004215998	likely pathogenic	Maple syrup urine disease	2023-02-10	criteria provided, single submitter	clinical testing