ClinVar Genomic variation as it relates to human health
NM_194454.3(KRIT1):c.1868G>A (p.Arg623His)
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.
Uncertain significance(2); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_194454.3(KRIT1):c.1868G>A (p.Arg623His)
Variation ID: 995332 Accession: VCV000995332.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q21.2 7: 92213352 (GRCh38) [ NCBI UCSC ] 7: 91842666 (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 Jan 26, 2021 May 1, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_194454.3:c.1868G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_919436.1:p.Arg623His missense NM_001013406.2:c.1724G>A NP_001013424.1:p.Arg575His missense NM_001350669.1:c.1724G>A NP_001337598.1:p.Arg575His missense NM_001350670.1:c.1724G>A NP_001337599.1:p.Arg575His missense NM_001350671.1:c.1154G>A NP_001337600.1:p.Arg385His missense NM_001350672.1:c.1868G>A NP_001337601.1:p.Arg623His missense NM_001350673.1:c.1868G>A NP_001337602.1:p.Arg623His missense NM_001350674.1:c.1868G>A NP_001337603.1:p.Arg623His missense NM_001350675.1:c.1868G>A NP_001337604.1:p.Arg623His missense NM_001350676.1:c.1868G>A NP_001337605.1:p.Arg623His missense NM_001350677.1:c.1868G>A NP_001337606.1:p.Arg623His missense NM_001350678.1:c.1868G>A NP_001337607.1:p.Arg623His missense NM_001350679.1:c.1868G>A NP_001337608.1:p.Arg623His missense NM_001350680.1:c.1868G>A NP_001337609.1:p.Arg623His missense NM_001350681.1:c.1868G>A NP_001337610.1:p.Arg623His missense NM_001350682.1:c.1868G>A NP_001337611.1:p.Arg623His missense NM_001350683.1:c.1868G>A NP_001337612.1:p.Arg623His missense NM_001350684.1:c.1868G>A NP_001337613.1:p.Arg623His missense NM_001350685.1:c.1868G>A NP_001337614.1:p.Arg623His missense NM_001350686.1:c.1868G>A NP_001337615.1:p.Arg623His missense NM_001350687.1:c.1868G>A NP_001337616.1:p.Arg623His missense NM_001350688.1:c.1868G>A NP_001337617.1:p.Arg623His missense NM_001350689.1:c.1868G>A NP_001337618.1:p.Arg623His missense NM_001350690.1:c.1868G>A NP_001337619.1:p.Arg623His missense NM_001350691.1:c.1868G>A NP_001337620.1:p.Arg623His missense NM_001350692.1:c.1868G>A NP_001337621.1:p.Arg623His missense NM_001350693.1:c.1868G>A NP_001337622.1:p.Arg623His missense NM_001350694.1:c.1868G>A NP_001337623.1:p.Arg623His missense NM_001350695.1:c.1868G>A NP_001337624.1:p.Arg623His missense NM_001350696.1:c.1868G>A NP_001337625.1:p.Arg623His missense NM_001350697.1:c.1868G>A NP_001337626.1:p.Arg623His missense NM_004912.4:c.1868G>A NP_004903.2:p.Arg623His missense NM_194455.1:c.1868G>A NP_919437.1:p.Arg623His missense NM_194456.1:c.1868G>A NP_919438.1:p.Arg623His missense NC_000007.14:g.92213352C>T NC_000007.13:g.91842666C>T NG_012964.1:g.37749G>A LRG_650:g.37749G>A LRG_650t1:c.1868G>A LRG_650p1:p.Arg623His - Protein change
- R385H, R575H, R623H
- Other names
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- Canonical SPDI
- NC_000007.14:92213351: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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0.00040 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00006
The Genome Aggregation Database (gnomAD), exomes 0.00008
The Genome Aggregation Database (gnomAD) 0.00012
Trans-Omics for Precision Medicine (TOPMed) 0.00014
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
- Links
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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KRIT1 | - | - |
GRCh38 GRCh37 |
620 | 649 |
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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Dec 14, 2020 | RCV001289361.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV003633583.1 | |
Likely benign (1) |
criteria provided, single submitter
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Oct 5, 2023 | RCV004035570.1 |
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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Likely benign
(Jan 21, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001477116.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Uncertain significance
(Dec 14, 2020)
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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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GeneDx
Accession: SCV001822272.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
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Uncertain significance
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cerebral cavernous malformation
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004471141.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 623 of the KRIT1 protein (p.Arg623His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 623 of the KRIT1 protein (p.Arg623His). This variant is present in population databases (rs143644029, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with KRIT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 995332). 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) performed at Invitae indicates that this missense variant is not expected to disrupt KRIT1 protein function with a negative predictive value of 80%. 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. (less)
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Likely benign
(Oct 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004894840.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs143644029 ...
HelpRecord last updated May 08, 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.