ClinVar Miner

Submissions for variant NM_000398.7(CYB5R3):c.173G>A (p.Arg58Gln)

gnomAD frequency: 0.00003  dbSNP: rs121965007
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002512600 SCV003444542 likely pathogenic not provided 2022-08-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 58 of the CYB5R3 protein (p.Arg58Gln). This variant is present in population databases (rs121965007, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with methemoglobinemia (PMID: 1707593, 24266649). This variant is also known as p.Arg57Gln. ClinVar contains an entry for this variant (Variation ID: 235). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CYB5R3 function (PMID: 1400360). This variant disrupts the p.Arg58 amino acid residue in CYB5R3. Other variant(s) that disrupt this residue have been observed in individuals with CYB5R3-related conditions (PMID: 1707593, 22627575, 24266649, 25058800), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV002512600 SCV005413412 likely pathogenic not provided 2023-06-20 criteria provided, single submitter clinical testing PP3, PM2_moderate, PM3, PS4_moderate
OMIM RCV000000259 SCV000020403 pathogenic METHEMOGLOBINEMIA, TYPE I 2008-05-01 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV003415596 SCV004116114 likely pathogenic CYB5R3-related disorder 2023-11-22 no assertion criteria provided clinical testing The CYB5R3 c.173G>A variant is predicted to result in the amino acid substitution p.Arg58Gln. This variant, previously reported as p.Arg57Gln using legacy nomenclature, has been reported in three homozygous and one compound heterozygous individuals with methemoglobinemia 1 (Katsube et al.1991. PubMed ID: 1707593; Shirabe et al. 1992. PubMed ID: 1400360; Warang et al. 2013. PubMed ID: 24266649). At PreventionGenetics, we have detected this variant in an individual with methemoglobinemia who had a second pathogenic variant, although phase was not determined (Internal Data). This variant is reported in 0.018% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic.

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