ClinVar Genomic variation as it relates to human health
NM_004387.4(NKX2-5):c.73C>T (p.Arg25Cys)
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(1); Benign(5); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004387.4(NKX2-5):c.73C>T (p.Arg25Cys)
Variation ID: 9008 Accession: VCV000009008.31
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q35.1 5: 173235011 (GRCh38) [ NCBI UCSC ] 5: 172662014 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 4, 2013 May 1, 2024 Jan 31, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_004387.4:c.73C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004378.1:p.Arg25Cys missense NM_001166175.2:c.73C>T NP_001159647.1:p.Arg25Cys missense NM_001166176.2:c.73C>T NP_001159648.1:p.Arg25Cys missense NC_000005.10:g.173235011G>A NC_000005.9:g.172662014G>A NG_013340.1:g.5302C>T LRG_671:g.5302C>T LRG_671t1:c.73C>T LRG_671p1:p.Arg25Cys P52952:p.Arg25Cys - Protein change
- R25C
- Other names
- p.R25C:CGC>TGC
- Canonical SPDI
- NC_000005.10:173235010:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.01018 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00343
Exome Aggregation Consortium (ExAC) 0.00363
1000 Genomes Project 0.01018
1000 Genomes Project 30x 0.01062
The Genome Aggregation Database (gnomAD) 0.01082
Trans-Omics for Precision Medicine (TOPMed) 0.01137
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 | ||
---|---|---|---|---|---|---|
HI score
Help
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. |
|||
NKX2-5 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
596 | 618 |
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. |
---|---|---|---|---|
Pathogenic (1) |
no assertion criteria provided
|
Aug 1, 2011 | RCV000009572.8 | |
Pathogenic (1) |
no assertion criteria provided
|
Aug 1, 2011 | RCV000009573.8 | |
Pathogenic (1) |
no assertion criteria provided
|
Aug 1, 2011 | RCV000023019.8 | |
Benign (1) |
no assertion criteria provided
|
Jun 4, 2015 | RCV000030339.4 | |
Pathogenic (1) |
no assertion criteria provided
|
Aug 1, 2011 | RCV000023018.10 | |
Pathogenic (1) |
no assertion criteria provided
|
Aug 1, 2011 | RCV000023017.8 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Sep 14, 2015 | RCV000037968.20 | |
Benign (1) |
criteria provided, single submitter
|
Aug 4, 2015 | RCV000619696.6 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV000987632.9 | |
Benign (1) |
criteria provided, single submitter
|
Jun 1, 2023 | RCV003311655.7 |
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. |
|
---|---|---|---|---|---|
Likely benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000310346.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
|
Uncertain significance
(Sep 14, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000194075.2
First in ClinVar: Nov 23, 2014 Last updated: Nov 10, 2017 |
|
|
Benign
(Jan 31, 2012)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061634.6
First in ClinVar: May 03, 2013 Last updated: Nov 10, 2017 |
Comment:
Arg25Cys in exon 1 of NKX2-5: This variant has been reported in a large number o f individuals with congenital heart disease (Akcaboy 2008, Benson … (more)
Arg25Cys in exon 1 of NKX2-5: This variant has been reported in a large number o f individuals with congenital heart disease (Akcaboy 2008, Benson 1999, DeLuca 2 010, Esposito 2009, Goli-Pereira 2010, Goldmuntz 2001, McElhinny 2003, Raunch 20 10, Stallmeyer 2010). This variant is now considered to be benign based on its h igh population frequency (2.6%) in the Black population (97/3694 chromosomes, NH LBI Exome Variant Project http://evs.gs.washington.edu/EVS/). (less)
Number of individuals with the variant: 2
|
|
Benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Atrial septal defect 7
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000262103.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
|
|
Benign
(Jun 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004011640.6
First in ClinVar: Jul 16, 2023 Last updated: Apr 15, 2024 |
Comment:
NKX2-5: BS1, BS2
Number of individuals with the variant: 1
|
|
Benign
(Aug 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000223572.7
First in ClinVar: May 23, 2015 Last updated: Nov 10, 2017 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
|
Likely benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Atrial septal defect 7
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001137025.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
Benign
(Aug 04, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000735169.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as 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)
|
|
Benign
(Jun 04, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Congenital heart disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000053006.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
|
|
Pathogenic
(Aug 01, 2011)
|
no assertion criteria provided
Method: literature only
|
HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 5
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029791.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 24, 2023 |
Comment on evidence:
Congenital Cardiac Defects In a female patient with tetralogy of Fallot (TOF; 187500) who was negative for del(22q11), Benson et al. (1999) identified heterozygosity for … (more)
Congenital Cardiac Defects In a female patient with tetralogy of Fallot (TOF; 187500) who was negative for del(22q11), Benson et al. (1999) identified heterozygosity for a 182C-T transition in the 5-prime coding region of the NKX2-5 gene, resulting in an arg25-to-cys (R25C) substitution that changes a highly conserved amino acid from basic to neutral. The mutation was not found in 100 control chromosomes from a randomly selected population. The patient, who had undergone surgical repair of typical TOF and 2 small muscular ventricular septal defects at 1 year of age, did not have atrioventricular block or atrial septal defect. Kasahara et al. (2000) demonstrated impaired DNA binding of the R25C variant CSX peptide to dimeric sites. Goldmuntz et al. (2001) identified the R25C mutation in 3 unrelated probands with tetralogy of Fallot who were negative for del(22q11). None of the patients had atrioventricular conduction abnormalities. The father of 1 of the probands was also heterozygous for the R25C mutation and had a history of ventricular septal defect. McElhinney et al. (2003) screened the NKX2-5 gene in 474 patients with congenital cardiac defects and identified heterozygosity for the R25C mutation in 1 (4%) of 23 patients with interrupted aortic arch (see 217095), 1 (4%) of 22 patients with truncus arteriosus (see 217095), and 1 (1%) of 80 patients with hypoplastic left heart syndrome (HLHS2; 614435). In 2 (0.9%) of 230 patients with TOF, Rauch et al. (2010) identified heterozygosity for the R25C mutation. In 1 of 9 patients with hypoplastic left heart syndrome, Stallmeyer et al. (2010) identified heterozygosity for the R25C mutation. The complete cardiac phenotype of the male infant included atresia of the aortic and mitral valves and a small VSD that required corrective surgery. In 2 sporadic Italian patients with TOF associated with a left-sided arch, subaortic ventricular septal defect, and patent pulmonary valve, De Luca et al. (2011) identified the R25C mutation in the NKX2-5 gene. Parental DNA was unavailable for analysis; the mutation was not found in 500 population-matched controls. Congenital Nongoitrous Hypothyroidism 5 In a 24-year-old woman with thyroid ectopy and a 15-year-old boy with athyreosis of the gland (see CHNG5, 225250), Dentice et al. (2006) identified a heterozygous 73C-T transition in the NKX2-5 gene, resulting in an R25C substitution. The mutation in each case was inherited from a parent. Neither patient had a history of cardiac disease; the boy showed bilateral cortex atrophy at birth and had attention deficit hyperactivity disorder. The mutation, which was identified in 1 of 561 control individuals, exhibited significant functional impairment, with reduction of transactivation properties and dominant-negative effect. In addition, the results indicated that although the R25C mutant normally also binds the DIO2 (601413) promoter, its activity on the DIO2, TG (188450), and TPO (606765) promoters is significantly impaired. (less)
|
|
Pathogenic
(Aug 01, 2011)
|
no assertion criteria provided
Method: literature only
|
TETRALOGY OF FALLOT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000029790.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 24, 2023 |
Comment on evidence:
Congenital Cardiac Defects In a female patient with tetralogy of Fallot (TOF; 187500) who was negative for del(22q11), Benson et al. (1999) identified heterozygosity for … (more)
Congenital Cardiac Defects In a female patient with tetralogy of Fallot (TOF; 187500) who was negative for del(22q11), Benson et al. (1999) identified heterozygosity for a 182C-T transition in the 5-prime coding region of the NKX2-5 gene, resulting in an arg25-to-cys (R25C) substitution that changes a highly conserved amino acid from basic to neutral. The mutation was not found in 100 control chromosomes from a randomly selected population. The patient, who had undergone surgical repair of typical TOF and 2 small muscular ventricular septal defects at 1 year of age, did not have atrioventricular block or atrial septal defect. Kasahara et al. (2000) demonstrated impaired DNA binding of the R25C variant CSX peptide to dimeric sites. Goldmuntz et al. (2001) identified the R25C mutation in 3 unrelated probands with tetralogy of Fallot who were negative for del(22q11). None of the patients had atrioventricular conduction abnormalities. The father of 1 of the probands was also heterozygous for the R25C mutation and had a history of ventricular septal defect. McElhinney et al. (2003) screened the NKX2-5 gene in 474 patients with congenital cardiac defects and identified heterozygosity for the R25C mutation in 1 (4%) of 23 patients with interrupted aortic arch (see 217095), 1 (4%) of 22 patients with truncus arteriosus (see 217095), and 1 (1%) of 80 patients with hypoplastic left heart syndrome (HLHS2; 614435). In 2 (0.9%) of 230 patients with TOF, Rauch et al. (2010) identified heterozygosity for the R25C mutation. In 1 of 9 patients with hypoplastic left heart syndrome, Stallmeyer et al. (2010) identified heterozygosity for the R25C mutation. The complete cardiac phenotype of the male infant included atresia of the aortic and mitral valves and a small VSD that required corrective surgery. In 2 sporadic Italian patients with TOF associated with a left-sided arch, subaortic ventricular septal defect, and patent pulmonary valve, De Luca et al. (2011) identified the R25C mutation in the NKX2-5 gene. Parental DNA was unavailable for analysis; the mutation was not found in 500 population-matched controls. Congenital Nongoitrous Hypothyroidism 5 In a 24-year-old woman with thyroid ectopy and a 15-year-old boy with athyreosis of the gland (see CHNG5, 225250), Dentice et al. (2006) identified a heterozygous 73C-T transition in the NKX2-5 gene, resulting in an R25C substitution. The mutation in each case was inherited from a parent. Neither patient had a history of cardiac disease; the boy showed bilateral cortex atrophy at birth and had attention deficit hyperactivity disorder. The mutation, which was identified in 1 of 561 control individuals, exhibited significant functional impairment, with reduction of transactivation properties and dominant-negative effect. In addition, the results indicated that although the R25C mutant normally also binds the DIO2 (601413) promoter, its activity on the DIO2, TG (188450), and TPO (606765) promoters is significantly impaired. (less)
|
|
Pathogenic
(Aug 01, 2011)
|
no assertion criteria provided
Method: literature only
|
INTERRUPTED AORTIC ARCH
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044308.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 24, 2023 |
Comment on evidence:
Congenital Cardiac Defects In a female patient with tetralogy of Fallot (TOF; 187500) who was negative for del(22q11), Benson et al. (1999) identified heterozygosity for … (more)
Congenital Cardiac Defects In a female patient with tetralogy of Fallot (TOF; 187500) who was negative for del(22q11), Benson et al. (1999) identified heterozygosity for a 182C-T transition in the 5-prime coding region of the NKX2-5 gene, resulting in an arg25-to-cys (R25C) substitution that changes a highly conserved amino acid from basic to neutral. The mutation was not found in 100 control chromosomes from a randomly selected population. The patient, who had undergone surgical repair of typical TOF and 2 small muscular ventricular septal defects at 1 year of age, did not have atrioventricular block or atrial septal defect. Kasahara et al. (2000) demonstrated impaired DNA binding of the R25C variant CSX peptide to dimeric sites. Goldmuntz et al. (2001) identified the R25C mutation in 3 unrelated probands with tetralogy of Fallot who were negative for del(22q11). None of the patients had atrioventricular conduction abnormalities. The father of 1 of the probands was also heterozygous for the R25C mutation and had a history of ventricular septal defect. McElhinney et al. (2003) screened the NKX2-5 gene in 474 patients with congenital cardiac defects and identified heterozygosity for the R25C mutation in 1 (4%) of 23 patients with interrupted aortic arch (see 217095), 1 (4%) of 22 patients with truncus arteriosus (see 217095), and 1 (1%) of 80 patients with hypoplastic left heart syndrome (HLHS2; 614435). In 2 (0.9%) of 230 patients with TOF, Rauch et al. (2010) identified heterozygosity for the R25C mutation. In 1 of 9 patients with hypoplastic left heart syndrome, Stallmeyer et al. (2010) identified heterozygosity for the R25C mutation. The complete cardiac phenotype of the male infant included atresia of the aortic and mitral valves and a small VSD that required corrective surgery. In 2 sporadic Italian patients with TOF associated with a left-sided arch, subaortic ventricular septal defect, and patent pulmonary valve, De Luca et al. (2011) identified the R25C mutation in the NKX2-5 gene. Parental DNA was unavailable for analysis; the mutation was not found in 500 population-matched controls. Congenital Nongoitrous Hypothyroidism 5 In a 24-year-old woman with thyroid ectopy and a 15-year-old boy with athyreosis of the gland (see CHNG5, 225250), Dentice et al. (2006) identified a heterozygous 73C-T transition in the NKX2-5 gene, resulting in an R25C substitution. The mutation in each case was inherited from a parent. Neither patient had a history of cardiac disease; the boy showed bilateral cortex atrophy at birth and had attention deficit hyperactivity disorder. The mutation, which was identified in 1 of 561 control individuals, exhibited significant functional impairment, with reduction of transactivation properties and dominant-negative effect. In addition, the results indicated that although the R25C mutant normally also binds the DIO2 (601413) promoter, its activity on the DIO2, TG (188450), and TPO (606765) promoters is significantly impaired. (less)
|
|
Pathogenic
(Aug 01, 2011)
|
no assertion criteria provided
Method: literature only
|
TRUNCUS ARTERIOSUS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044309.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 24, 2023 |
Comment on evidence:
Congenital Cardiac Defects In a female patient with tetralogy of Fallot (TOF; 187500) who was negative for del(22q11), Benson et al. (1999) identified heterozygosity for … (more)
Congenital Cardiac Defects In a female patient with tetralogy of Fallot (TOF; 187500) who was negative for del(22q11), Benson et al. (1999) identified heterozygosity for a 182C-T transition in the 5-prime coding region of the NKX2-5 gene, resulting in an arg25-to-cys (R25C) substitution that changes a highly conserved amino acid from basic to neutral. The mutation was not found in 100 control chromosomes from a randomly selected population. The patient, who had undergone surgical repair of typical TOF and 2 small muscular ventricular septal defects at 1 year of age, did not have atrioventricular block or atrial septal defect. Kasahara et al. (2000) demonstrated impaired DNA binding of the R25C variant CSX peptide to dimeric sites. Goldmuntz et al. (2001) identified the R25C mutation in 3 unrelated probands with tetralogy of Fallot who were negative for del(22q11). None of the patients had atrioventricular conduction abnormalities. The father of 1 of the probands was also heterozygous for the R25C mutation and had a history of ventricular septal defect. McElhinney et al. (2003) screened the NKX2-5 gene in 474 patients with congenital cardiac defects and identified heterozygosity for the R25C mutation in 1 (4%) of 23 patients with interrupted aortic arch (see 217095), 1 (4%) of 22 patients with truncus arteriosus (see 217095), and 1 (1%) of 80 patients with hypoplastic left heart syndrome (HLHS2; 614435). In 2 (0.9%) of 230 patients with TOF, Rauch et al. (2010) identified heterozygosity for the R25C mutation. In 1 of 9 patients with hypoplastic left heart syndrome, Stallmeyer et al. (2010) identified heterozygosity for the R25C mutation. The complete cardiac phenotype of the male infant included atresia of the aortic and mitral valves and a small VSD that required corrective surgery. In 2 sporadic Italian patients with TOF associated with a left-sided arch, subaortic ventricular septal defect, and patent pulmonary valve, De Luca et al. (2011) identified the R25C mutation in the NKX2-5 gene. Parental DNA was unavailable for analysis; the mutation was not found in 500 population-matched controls. Congenital Nongoitrous Hypothyroidism 5 In a 24-year-old woman with thyroid ectopy and a 15-year-old boy with athyreosis of the gland (see CHNG5, 225250), Dentice et al. (2006) identified a heterozygous 73C-T transition in the NKX2-5 gene, resulting in an R25C substitution. The mutation in each case was inherited from a parent. Neither patient had a history of cardiac disease; the boy showed bilateral cortex atrophy at birth and had attention deficit hyperactivity disorder. The mutation, which was identified in 1 of 561 control individuals, exhibited significant functional impairment, with reduction of transactivation properties and dominant-negative effect. In addition, the results indicated that although the R25C mutant normally also binds the DIO2 (601413) promoter, its activity on the DIO2, TG (188450), and TPO (606765) promoters is significantly impaired. (less)
|
|
Pathogenic
(Aug 01, 2011)
|
no assertion criteria provided
Method: literature only
|
HYPOPLASTIC LEFT HEART SYNDROME 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000044310.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 24, 2023 |
Comment on evidence:
Congenital Cardiac Defects In a female patient with tetralogy of Fallot (TOF; 187500) who was negative for del(22q11), Benson et al. (1999) identified heterozygosity for … (more)
Congenital Cardiac Defects In a female patient with tetralogy of Fallot (TOF; 187500) who was negative for del(22q11), Benson et al. (1999) identified heterozygosity for a 182C-T transition in the 5-prime coding region of the NKX2-5 gene, resulting in an arg25-to-cys (R25C) substitution that changes a highly conserved amino acid from basic to neutral. The mutation was not found in 100 control chromosomes from a randomly selected population. The patient, who had undergone surgical repair of typical TOF and 2 small muscular ventricular septal defects at 1 year of age, did not have atrioventricular block or atrial septal defect. Kasahara et al. (2000) demonstrated impaired DNA binding of the R25C variant CSX peptide to dimeric sites. Goldmuntz et al. (2001) identified the R25C mutation in 3 unrelated probands with tetralogy of Fallot who were negative for del(22q11). None of the patients had atrioventricular conduction abnormalities. The father of 1 of the probands was also heterozygous for the R25C mutation and had a history of ventricular septal defect. McElhinney et al. (2003) screened the NKX2-5 gene in 474 patients with congenital cardiac defects and identified heterozygosity for the R25C mutation in 1 (4%) of 23 patients with interrupted aortic arch (see 217095), 1 (4%) of 22 patients with truncus arteriosus (see 217095), and 1 (1%) of 80 patients with hypoplastic left heart syndrome (HLHS2; 614435). In 2 (0.9%) of 230 patients with TOF, Rauch et al. (2010) identified heterozygosity for the R25C mutation. In 1 of 9 patients with hypoplastic left heart syndrome, Stallmeyer et al. (2010) identified heterozygosity for the R25C mutation. The complete cardiac phenotype of the male infant included atresia of the aortic and mitral valves and a small VSD that required corrective surgery. In 2 sporadic Italian patients with TOF associated with a left-sided arch, subaortic ventricular septal defect, and patent pulmonary valve, De Luca et al. (2011) identified the R25C mutation in the NKX2-5 gene. Parental DNA was unavailable for analysis; the mutation was not found in 500 population-matched controls. Congenital Nongoitrous Hypothyroidism 5 In a 24-year-old woman with thyroid ectopy and a 15-year-old boy with athyreosis of the gland (see CHNG5, 225250), Dentice et al. (2006) identified a heterozygous 73C-T transition in the NKX2-5 gene, resulting in an R25C substitution. The mutation in each case was inherited from a parent. Neither patient had a history of cardiac disease; the boy showed bilateral cortex atrophy at birth and had attention deficit hyperactivity disorder. The mutation, which was identified in 1 of 561 control individuals, exhibited significant functional impairment, with reduction of transactivation properties and dominant-negative effect. In addition, the results indicated that although the R25C mutant normally also binds the DIO2 (601413) promoter, its activity on the DIO2, TG (188450), and TPO (606765) promoters is significantly impaired. (less)
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
New mutations in ZFPM2/FOG2 gene in tetralogy of Fallot and double outlet right ventricle. | De Luca A | Clinical genetics | 2011 | PMID: 20807224 |
Mutational spectrum in the cardiac transcription factor gene NKX2.5 (CSX) associated with congenital heart disease. | Stallmeyer B | Clinical genetics | 2010 | PMID: 20456451 |
Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot. | Rauch R | Journal of medical genetics | 2010 | PMID: 19948535 |
NKX2.5 mutations in patients with non-syndromic congenital heart disease. | Gioli-Pereira L | International journal of cardiology | 2010 | PMID: 19073351 |
Molecular analysis of PRKAG2, LAMP2, and NKX2-5 genes in a cohort of 125 patients with accessory atrioventricular connection. | Esposito G | American journal of medical genetics. Part A | 2009 | PMID: 19533775 |
Mutations in the NKX2-5 gene in patients with stroke and patent foramen ovale. | Belvís R | Clinical neurology and neurosurgery | 2009 | PMID: 19464101 |
The effect of p.Arg25Cys alteration in NKX2-5 on conotruncal heart anomalies: mutation or polymorphism? | Akçaboy MI | Pediatric cardiology | 2008 | PMID: 17891434 |
Missense mutation in the transcription factor NKX2-5: a novel molecular event in the pathogenesis of thyroid dysgenesis. | Dentice M | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16418214 |
NKX2.5 mutations in patients with congenital heart disease. | McElhinney DB | Journal of the American College of Cardiology | 2003 | PMID: 14607454 |
NKX2.5 mutations in patients with tetralogy of fallot. | Goldmuntz E | Circulation | 2001 | PMID: 11714651 |
Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease. | Kasahara H | The Journal of clinical investigation | 2000 | PMID: 10903346 |
Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. | Benson DW | The Journal of clinical investigation | 1999 | PMID: 10587520 |
click to load more click to collapse |
Text-mined citations for rs28936670 ...
HelpRecord last updated May 01, 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.