ClinVar Genomic variation as it relates to human health
NM_000398.7(CYB5R3):c.757G>A (p.Val253Met)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000398.7(CYB5R3):c.757G>A (p.Val253Met)
Variation ID: 505719 Accession: VCV000505719.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.2 22: 42619922 (GRCh38) [ NCBI UCSC ] 22: 43015928 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 9, 2018 Jun 17, 2024 Aug 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000398.7:c.757G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000389.1:p.Val253Met missense NM_001129819.2:c.688G>A NP_001123291.1:p.Val230Met missense NM_001171660.2:c.856G>A NP_001165131.1:p.Val286Met missense NM_001171661.1:c.688G>A NP_001165132.1:p.Val230Met missense NM_007326.4:c.688G>A NP_015565.1:p.Val230Met missense NC_000022.11:g.42619922C>T NC_000022.10:g.43015928C>T NG_012194.1:g.34478G>A - Protein change
- V253M, V286M, V230M
- Other names
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- Canonical SPDI
- NC_000022.11:42619921:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00010
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
Exome Aggregation Consortium (ExAC) 0.00019
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CYB5R3 | - | - |
GRCh38 GRCh37 |
194 | 249 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Mar 30, 2020 | RCV000601950.13 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Aug 28, 2023 | RCV001811091.23 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 25, 2023 | RCV002498895.11 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Mar 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary methemoglobinemia
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000713108.2
First in ClinVar: Apr 09, 2018 Last updated: Jul 03, 2020 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 1
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Pathogenic
(Mar 18, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002048450.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
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Pathogenic
(Jul 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of cytochrome-b5 reductase
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002810422.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: not provided
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Deficiency of cytochrome-b5 reductase
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004046673.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
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Pathogenic
(Feb 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of cytochrome-b5 reductase
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004235467.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Aug 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002119488.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CYB5R3 function (PMID: 16310381). This sequence … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CYB5R3 function (PMID: 16310381). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 253 of the CYB5R3 protein (p.Val253Met). This variant is present in population databases (rs144071404, gnomAD 0.01%). This missense change has been observed in individuals with methemoglobinemia (PMID: 11159544, 11295830, 12756024, 16310381, 21349748). It has also been observed to segregate with disease in related individuals. This variant is also known as V252M. ClinVar contains an entry for this variant (Variation ID: 505719). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CYB5R3 protein function. (less)
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Pathogenic
(Jul 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004033956.7
First in ClinVar: Sep 16, 2023 Last updated: Jun 17, 2024 |
Comment:
CYB5R3: PM3:Strong, PP1:Strong, PM2, PS3:Supporting
Number of individuals with the variant: 1
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Molecular basis of two novel mutations found in type I methemoglobinemia. | Lorenzo FR 5th | Blood cells, molecules & diseases | 2011 | PMID: 21349748 |
Identification and characterization of the novel FAD-binding lobe G75S mutation in cytochrome b(5) reductase: an aid to determine recessive congenital methemoglobinemia status in an infant. | Percy MJ | Blood cells, molecules & diseases | 2006 | PMID: 16310381 |
Compound heterozygosity of two missense mutations in the NADH-cytochrome b5 reductase gene of a Polish patient with type I recessive congenital methaemoglobinaemia. | Grabowska D | European journal of haematology | 2003 | PMID: 12756024 |
Molecular basis of recessive congenital methemoglobinemia, types I and II: Exon skipping and three novel missense mutations in the NADH-cytochrome b5 reductase (diaphorase 1) gene. | Kugler W | Human mutation | 2001 | PMID: 11295830 |
Seven new mutations in the nicotinamide adenine dinucleotide reduced-cytochrome b(5) reductase gene leading to methemoglobinemia type I. | Dekker J | Blood | 2001 | PMID: 11159544 |
Text-mined citations for rs144071404 ...
HelpRecord last updated Jun 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.