Submissions for variant NM_015713.5(RRM2B):c.446C>T (p.Pro149Leu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003841627	SCV004693101	uncertain significance	not provided	2023-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 149 of the RRM2B protein (p.Pro149Leu). This variant is present in population databases (rs752230983, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RRM2B-related conditions. 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 not expected to disrupt RRM2B protein function. 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.
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	RCV004720403	SCV005326563	uncertain significance	Mitochondrial DNA depletion syndrome 8a	2024-09-25	criteria provided, single submitter	research	The highest population allele frequency in gnomAD v4.0 is 0.0002306 (21/91070 alleles) in South Asian population including 1 homozygous observation. PP3 Not Met: REVEL score is 0.56. PM3_Supporting: 0.5 points awarded for homozygous observation of variant in proband under assessment. PS4 Not Met: Variant detected in the heterozygous state in 3 probands who underwent clinical testing for phenotypes unrelated to this curation. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases.