ClinVar Genomic variation as it relates to human health
NM_004387.4(NKX2-5):c.355G>T (p.Ala119Ser)
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.355G>T (p.Ala119Ser)
Variation ID: 9018 Accession: VCV000009018.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q35.1 5: 173233189 (GRCh38) [ NCBI UCSC ] 5: 172660192 (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 Dec 7, 2014 May 1, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004387.4:c.355G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004378.1:p.Ala119Ser missense NM_001166175.2:c.*308G>T 3 prime UTR NM_001166176.2:c.*154G>T 3 prime UTR NC_000005.10:g.173233189C>A NC_000005.9:g.172660192C>A NG_013340.1:g.7124G>T LRG_671:g.7124G>T LRG_671t1:c.355G>T LRG_671p1:p.Ala119Ser P52952:p.Ala119Ser - Protein change
- A119S
- Other names
- p.A119S:GCG>TCG
- Canonical SPDI
- NC_000005.10:173233188:C: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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0.00060 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
Trans-Omics for Precision Medicine (TOPMed) 0.00063
The Genome Aggregation Database (gnomAD), exomes 0.00090
Exome Aggregation Consortium (ExAC) 0.00122
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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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. |
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Pathogenic (1) |
no assertion criteria provided
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Apr 1, 2006 | RCV000009584.5 | |
Benign (1) |
criteria provided, single submitter
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Apr 2, 2018 | RCV000171007.7 | |
Benign (1) |
criteria provided, single submitter
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Feb 1, 2024 | RCV000230156.13 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 19, 2022 | RCV000620259.4 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Nov 1, 2022 | RCV001529235.15 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 5, 2021 | RCV003904824.1 |
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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Benign
(Apr 02, 2018)
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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: SCV000917901.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: NKX2-5 c.355G>T (p.Ala119Ser) 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.355G>T (p.Ala119Ser) 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 0.00097 in 259522 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 194.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NKX2-5 causing Congenital Heart Disease phenotype (5e-06), strongly suggesting that the variant is benign. The variant, c.355G>T has been reported in the literature in individuals affected with Congenital Heart Disease, and the same publication reports experimental evidence evaluating an impact on protein function that showed variant behaves equal to wildtype NKX2-5 (vanEngelen_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
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Benign
(Feb 01, 2024)
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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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Invitae
Accession: SCV000288517.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
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Likely benign
(Mar 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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NKX2-5-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004720721.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Benign
(Nov 01, 2022)
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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: SCV002545376.10
First in ClinVar: Jul 09, 2022 Last updated: Apr 15, 2024 |
Comment:
NKX2-5: BS1, BS2
Number of individuals with the variant: 3
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Likely benign
(Sep 25, 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: SCV000223570.14
First in ClinVar: May 23, 2015 Last updated: Apr 09, 2018 |
Comment:
This variant is associated with the following publications: (PMID: 23285148, 24376681, 23661673, 27207958, 16418214, 28387797, 28798025, 31147515)
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Likely benign
(Jan 19, 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: SCV000735072.5
First in ClinVar: Apr 14, 2018 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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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001742342.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001917127.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001970120.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Pathogenic
(Apr 01, 2006)
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no assertion criteria provided
Method: literature only
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HYPOTHYROIDISM, CONGENITAL, NONGOITROUS, 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000029802.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 24, 2023 |
Comment on evidence:
In a 13-year-old girl with an ectopic thyroid and severe hypothyroidism (CHNG5; 225250), who had no documented congenital heart defect, Dentice et al. (2006) identified … (more)
In a 13-year-old girl with an ectopic thyroid and severe hypothyroidism (CHNG5; 225250), who had no documented congenital heart defect, Dentice et al. (2006) identified a heterozygous 335G-T transversion in the NXK2E gene, resulting in an ala119-to-ser substitution a few residues upstream from the beginning of the homeodomain. The mutation was inherited from the mother, who exhibited autoimmune hypothyroidism and was on lifelong treatment with L-T4, and was not observed among 561 controls. The mutation exhibited a significant functional impairment, with reduction of transactivation properties and dominant-negative effect, which was associated with reduced DNA binding. (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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The ambiguous role of NKX2-5 mutations in thyroid dysgenesis. | van Engelen K | PloS one | 2012 | PMID: 23285148 |
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 |
Text-mined citations for rs137852684 ...
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.