ClinVar Genomic variation as it relates to human health
NM_172351.3(CD46):c.643G>A (p.Val215Met)
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_172351.3(CD46):c.643G>A (p.Val215Met)
Variation ID: 1049467 Accession: VCV001049467.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.2 1: 207761416 (GRCh38) [ NCBI UCSC ] 1: 207934761 (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 13, 2021 Feb 14, 2024 Jun 27, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_172351.3:c.643G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_758861.1:p.Val215Met missense NM_002389.4:c.643G>A NP_002380.3:p.Val215Met missense NM_153826.4:c.643G>A NP_722548.1:p.Val215Met missense NM_172350.3:c.643G>A NP_758860.1:p.Val215Met missense NM_172352.3:c.643G>A NP_758862.1:p.Val215Met missense NM_172353.3:c.643G>A NP_758863.1:p.Val215Met missense NM_172355.3:c.643G>A NP_758865.1:p.Val215Met missense NM_172356.3:c.643G>A NP_758866.1:p.Val215Met missense NM_172357.3:c.643G>A NP_758867.1:p.Val215Met missense NM_172358.3:c.643G>A NP_758868.1:p.Val215Met missense NM_172359.3:c.643G>A NP_758869.1:p.Val215Met missense NM_172361.3:c.643G>A NP_758871.1:p.Val215Met missense NC_000001.11:g.207761416G>A NC_000001.10:g.207934761G>A NG_009296.1:g.14360G>A LRG_155:g.14360G>A LRG_155t1:c.643G>A LRG_155p1:p.Val215Met - Protein change
- V215M
- Other names
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- Canonical SPDI
- NC_000001.11:207761415:G:A
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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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00003
Exome Aggregation Consortium (ExAC) 0.00005
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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
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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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CD46 | - | - |
GRCh38 GRCh37 |
322 | 370 |
Conditions - Germline
Condition
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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
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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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Uncertain significance (2) |
criteria provided, single submitter
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Jun 27, 2022 | RCV001355611.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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- | RCV003339613.2 |
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
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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
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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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Uncertain significance
(-)
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criteria provided, single submitter
Method: clinical testing
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Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004048460.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
The missense variant in c.643G>A (p.Val215Met) in CD46 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our … (more)
The missense variant in c.643G>A (p.Val215Met) in CD46 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This Variant has an allele frequency of 0.003181% in gnomAD database. In silico tools predict the variant to be tolerated. The amino acid Val at position 215 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Uncertain Significance (VUS). (less)
Clinical Features:
Vomiting (present) , Headache (present) , Hemolytic-uremic syndrome (present)
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Uncertain significance
(Jun 27, 2022)
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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: SCV003523377.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 215 of the CD46 protein (p.Val215Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 215 of the CD46 protein (p.Val215Met). This variant is present in population databases (rs535353049, gnomAD 0.02%). 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. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1049467). This missense change has been observed in individual(s) with primary glomerulonephritis (PMID: 17018561). (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550544.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The CD46 p.Val215Met variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in … (more)
The CD46 p.Val215Met variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs535353049) and in control databases in 8 of 251466 chromosomes at a frequency of 0.000032 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 7 of 30614 chromosomes (freq: 0.000229) and European (non-Finnish) in 1 of 113748 chromosomes (freq: 0.000009), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and Other populations. The p.Val215 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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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Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. | Servais A | Journal of medical genetics | 2007 | PMID: 17018561 |
Text-mined citations for rs535353049 ...
HelpRecord last updated Apr 06, 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.