ClinVar Miner

Submissions for variant NM_000398.7(CYB5R3):c.464-2A>C

gnomAD frequency: 0.00004  dbSNP: rs794728013
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mendelics RCV000986216 SCV001135144 pathogenic Deficiency of cytochrome-b5 reductase 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001390260 SCV001591936 pathogenic not provided 2018-05-16 criteria provided, single submitter clinical testing This variant has been observed in individuals affected with recessive congenital methemoglobinemia (RCM) type II (PMID: 15921385, 9266404). ClinVar contains an entry for this variant (Variation ID: 245). For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CYB5R3 are known to be pathogenic (PMID: 18318771). Experimental studies have shown that this intronic change causes aberrant splicing of the CYB5R3 mRNA (PMID: 9266404). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 5 of the CYB5R3 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
GeneDx RCV001390260 SCV002756852 likely pathogenic not provided 2022-05-05 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing, and in vitro studies demonstrate altered splicing (Maran et al., 2005); This variant is associated with the following publications: (PMID: 31898843, 25525159, 15921385, 15744830, 9266404)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000986216 SCV003807994 pathogenic Deficiency of cytochrome-b5 reductase 2022-07-05 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 moderated, PM2 moderated, PM3 moderated, PP4
OMIM RCV000000269 SCV000020413 pathogenic Methemoglobinemia type 2 2005-05-01 no assertion criteria provided literature only

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