ClinVar Miner

Submissions for variant NM_015713.5(RRM2B):c.686G>T (p.Gly229Val)

gnomAD frequency: 0.00002  dbSNP: rs121918311
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001818139 SCV002064404 pathogenic not provided 2020-01-26 criteria provided, single submitter clinical testing DNA sequence analysis of the RRM2B gene demonstrated a sequence change, c.686G>T, in exon 7 that results in an amino acid change, p.Gly229Val. This sequence change has been previously reported in a homozygous state in two siblings with severe muscular hypotonia, seizures, poor visual contact, feeding difficulties, failure to thrive, lactic acidosis and proximal renal tubulopathy in one sibling (PMID: 19138848). Each unaffected parent was heterozygous for the change. Southern blot analysis of patient's muscle tissue showed severe mtDNA depletion, about 1 to 4% of normal controls. This sequence change has been described in the gnomAD database with a low overall population frequency of 0.0016% (dbSNP rs121918311); however it has not been observed in the homozygous state in any individuals. The p.Gly229Val change affects a highly conserved amino acid residue located in a diferric iron center of the ribonucleotide reductase or RRM2B protein that is known to be functional. The p.Gly229Val substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). These collective evidences indicate that this sequence change is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001818139 SCV002211890 uncertain significance not provided 2023-05-15 criteria provided, single submitter clinical testing An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 5392). This missense change has been observed in individuals with clinical features of RRM2B-related conditions (PMID: 19138848, 21646632, 27290639, 33300680). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918311, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 229 of the RRM2B protein (p.Gly229Val). 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.
Mayo Clinic Laboratories, Mayo Clinic RCV001818139 SCV005413864 likely pathogenic not provided 2024-05-31 criteria provided, single submitter clinical testing PP1_moderate, PP3, PM3_strong, PS4_moderate
OMIM RCV000005723 SCV000025905 pathogenic Mitochondrial DNA depletion syndrome 8a 2009-02-01 no assertion criteria provided literature only
GeneReviews RCV000119005 SCV000153703 not provided RRM2B-related mitochondrial disease no assertion provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.