ClinVar Genomic variation as it relates to human health
NM_004387.4(NKX2-5):c.65A>G (p.Gln22Arg)
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_004387.4(NKX2-5):c.65A>G (p.Gln22Arg)
Variation ID: 190840 Accession: VCV000190840.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q35.1 5: 173235019 (GRCh38) [ NCBI UCSC ] 5: 172662022 (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 Oct 5, 2015 Jul 23, 2024 Dec 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004387.4:c.65A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004378.1:p.Gln22Arg missense NM_001166175.2:c.65A>G NP_001159647.1:p.Gln22Arg missense NM_001166176.2:c.65A>G NP_001159648.1:p.Gln22Arg missense NC_000005.10:g.173235019T>C NC_000005.9:g.172662022T>C NG_013340.1:g.5294A>G LRG_671:g.5294A>G LRG_671t1:c.65A>G LRG_671p1:p.Gln22Arg - Protein change
- Q22R
- Other names
- p.Q22R:CAG>CGG
- Canonical SPDI
- NC_000005.10:173235018:T:C
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00016
Exome Aggregation Consortium (ExAC) 0.00018
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
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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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NKX2-5 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
616 | 639 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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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no classifications from unflagged records (1) |
no classifications from unflagged records
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Nov 17, 2023 | RCV000193266.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2023 | RCV000477570.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Oct 14, 2022 | RCV000618509.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Apr 30, 2021 | RCV000727462.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Sep 24, 2022 | RCV002298499.1 |
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
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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
(May 26, 2017)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000708745.2
First in ClinVar: May 29, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Apr 30, 2021)
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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: SCV000223581.14
First in ClinVar: May 23, 2015 Last updated: Apr 17, 2019 |
Comment:
Identified in a patient with an atrial septal defect in published literature (Draus et al., 2009); In silico analysis, which includes protein predictors and evolutionary … (more)
Identified in a patient with an atrial septal defect in published literature (Draus et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 190840; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 20725931, 19181906, 33835496) (less)
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Uncertain significance
(Dec 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Atrial septal defect 7
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000551863.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 22 of the NKX2-5 protein (p.Gln22Arg). … (more)
This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 22 of the NKX2-5 protein (p.Gln22Arg). This variant is present in population databases (rs201442000, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with an atrial septal defect (PMID: 19181906). ClinVar contains an entry for this variant (Variation ID: 190840). 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 NKX2-5 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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Uncertain significance
(Oct 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000736674.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
The p.Q22R variant (also known as c.65A>G), located in coding exon 1 of the NKX2-5 gene, results from an A to G substitution at nucleotide … (more)
The p.Q22R variant (also known as c.65A>G), located in coding exon 1 of the NKX2-5 gene, results from an A to G substitution at nucleotide position 65. The glutamine at codon 22 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in one individual with an atrial septal defect (Draus JM, J. Med. Genet. 2009 Feb; 46(2):115-22). This amino acid position is well conserved in available vertebrate species; however, arginine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (less)
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Uncertain significance
(Sep 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002598786.1
First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022 |
Comment:
Variant summary: NKX2-5 c.65A>G (p.Gln22Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: NKX2-5 c.65A>G (p.Gln22Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 243024 control chromosomes (gnomAD), predominantly at a frequency of 0.00026 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 52 fold of the estimated maximal expected allele frequency for a pathogenic variant in NKX2-5 causing Congenital Heart Disease (5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.65A>G has been reported in the literature in individuals affected with Atrial Septal Defects (Draus_2009) and Left Bundle Branch Block (Kohli_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: all classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Atrial septal defect 7
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557780.2
First in ClinVar: Aug 04, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with NKX2-5-related diseases, including atrial septal defect 7, with or without AV conduction defects (MIM#108900) and tetralogy of fallot (MIM#187500). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to arginine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (33 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v3) (10 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. These variants (p.Gln22Lys, p.Gln22Glu) have been reported as VUS and in a family with atrial septal defect (ASD) and congenital heart disease (CHD). An additional missense variant (p.Gln22Pro) with a stronger Grantham change has also been reported as both a VUS and as pathogenic, and has been observed in a patient with CHD and tetralogy of fallot (TOF) (LOVD, ClinVar, PMID: 22179962, PMID: 31824610). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as likely pathogenic and more commonly as a VUS, and has been observed in several patients with ASD and TOF (LOVD, ClinVar, PMID: 31824610, PMID: 19181906). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely pathogenic
(Feb 08, 2013)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Malformation of the heart and great vessels
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000248255.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more |
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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Isolated left bundle branch block in the young: case reports and review of literature. | Kohli U | Pacing and clinical electrophysiology : PACE | 2021 | PMID: 33835496 |
A comprehensive in silico analysis, distribution and frequency of human Nkx2-5 mutations; A critical gene in congenital heart disease. | Kalayinia S | Journal of cardiovascular and thoracic research | 2019 | PMID: 31824610 |
Novel NKX2-5 mutations responsible for congenital heart disease. | Wang J | Genetics and molecular research : GMR | 2011 | PMID: 22179962 |
Investigation of somatic NKX2-5 mutations in congenital heart disease. | Draus JM Jr | Journal of medical genetics | 2009 | PMID: 19181906 |
NKX2.5 mutations in patients with congenital heart disease. | McElhinney DB | Journal of the American College of Cardiology | 2003 | PMID: 14607454 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NKX2-5 | - | - | - | - |
Text-mined citations for rs201442000 ...
HelpRecord last updated Sep 29, 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.