ClinVar Genomic variation as it relates to human health
NM_018055.5(NODAL):c.778G>A (p.Gly260Arg)
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.
Likely pathogenic(2); Uncertain significance(5); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_018055.5(NODAL):c.778G>A (p.Gly260Arg)
Variation ID: 8269 Accession: VCV000008269.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q22.1 10: 70435399 (GRCh38) [ NCBI UCSC ] 10: 72195155 (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 4, 2013 Feb 14, 2024 Nov 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018055.5:c.778G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060525.3:p.Gly260Arg missense NM_001329906.2:c.379G>A NP_001316835.1:p.Gly127Arg missense NC_000010.11:g.70435399C>T NC_000010.10:g.72195155C>T NG_012448.2:g.17550G>A Q96S42:p.Gly260Arg - Protein change
- G260R, G127R
- Other names
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- Canonical SPDI
- NC_000010.11:70435398: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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00031
Exome Aggregation Consortium (ExAC) 0.00035
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00015
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
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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
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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NODAL | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
143 | 161 |
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
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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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Nov 13, 2023 | RCV000008758.30 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 3, 2015 | RCV000622859.10 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 14, 2017 | RCV000656169.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 16, 2023 | RCV001558244.13 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 29, 2017 | RCV001824117.9 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 31, 2023 | RCV003398472.4 |
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
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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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Likely pathogenic
(Aug 29, 2017)
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criteria provided, single submitter
Method: clinical testing
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heterotaxia syndrome
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996070.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
This missense variant is predicted to lead to decreased NODAL activity. This variant was previously described in 8/82 Hispanic patients with heterotaxy syndrome and severe … (more)
This missense variant is predicted to lead to decreased NODAL activity. This variant was previously described in 8/82 Hispanic patients with heterotaxy syndrome and severe congenital heart disease. This variant has an autosomal dominant transmission with reduced penetrance and variable expressivity (PMID: 19064609). It has a very low allele frequency in gnomAD (0.000278) and is almost exclusively seen in the Hispanic population. Based on the combined evidence of the literature and potential functional effects of this missense variant, the p.Gly260Arg variant is classified as likely pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Apr 03, 2015)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000740871.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Abnormal heart morphology (present) , Situs ambiguus (present) , Dilatation of the renal pelvis (present) , Abnormal form of the vertebral bodies (present) , Respiratory … (more)
Abnormal heart morphology (present) , Situs ambiguus (present) , Dilatation of the renal pelvis (present) , Abnormal form of the vertebral bodies (present) , Respiratory distress (present) , Feeding difficulties (present) , Lactic acidosis (present) , Vomiting (present) , Crumpled ear (present) (less)
Sex: male
Ethnicity/Population group: Hispanic
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Uncertain significance
(Jan 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Heterotaxy, visceral, 5, autosomal
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Genomic Medicine Lab, University of California San Francisco
Study: CSER-P3EGS
Accession: SCV001573085.1 First in ClinVar: May 05, 2021 Last updated: May 05, 2021 |
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Uncertain significance
(Jan 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Heterotaxy, visceral, 5, autosomal
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002050203.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The NODAL c.778G>A; p.Gly260Arg variant (rs121909283) is reported in the literature in multiple individuals affected with heterotaxy or cardiovascular malformations, although it has also been … (more)
The NODAL c.778G>A; p.Gly260Arg variant (rs121909283) is reported in the literature in multiple individuals affected with heterotaxy or cardiovascular malformations, although it has also been observed in healthy relatives and controls (Kingsmore 2019, Mohapatra 2009). This variant is found in the Latino population with an overall allele frequency of 0.22% (78/35440 alleles) in the Genome Aggregation Database. The glycine at codon 260 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.793). Functional studies suggest that the variant protein has mildly reduced transcriptional activation activity relative to wildtype NODAL, but the clinical relevance of these effects is unclear (Mohapatra 2009, Roessler 2009). Due to limited and conflicting information, the clinical significance of the p.Gly260Arg variant is uncertain at this time. References: Kingsmore et al. A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants. Am J Hum Genet. 2019 Oct 3;105(4):719-733. Mohapatra B et al. Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. Hum Mol Genet. 2009 Mar 1;18(5):861-71. Roessler E et al. Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly. Mol Genet Metab. 2009 Sep-Oct;98(1-2):225-34. (less)
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Uncertain significance
(Dec 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Heterotaxy, visceral, 5, autosomal
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001520332.2
First in ClinVar: Mar 22, 2021 Last updated: Mar 11, 2023 |
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Uncertain significance
(Mar 16, 2023)
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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: SCV001780150.4
First in ClinVar: Aug 12, 2021 Last updated: Mar 26, 2023 |
Comment:
Identified in multiple patients with complex congenital heart defects and heterotaxy or situs inversus referred for genetic testing at GeneDx and in published literature (Mohapatra … (more)
Identified in multiple patients with complex congenital heart defects and heterotaxy or situs inversus referred for genetic testing at GeneDx and in published literature (Mohapatra et al., 2009; Hagen et al., 2016; Clark et al., 2019); Published functional studies about the effect of this variant on NODAL signaling are conflicting (Mohapatra et al., 2009; Roessler et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19933292, 19553149, 22352765, 28738792, 27637763, 31019026, 31564432, 19064609) (less)
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Uncertain significance
(Jul 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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NODAL-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004105165.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The NODAL c.778G>A variant is predicted to result in the amino acid substitution p.Gly260Arg. In one study this variant was reported in eight Hispanic individuals … (more)
The NODAL c.778G>A variant is predicted to result in the amino acid substitution p.Gly260Arg. In one study this variant was reported in eight Hispanic individuals with transposition of the great arteries (TGA); however, in one individual it was inherited from an unaffected parent and was found in one Hispanic control sample (Mohapatra et al. 2009. PubMed ID: 19064609) Additionally, it has been reported as inherited in an individual with TGA (Family 213 in Table S2/S15 - Clark et al. 2019. PubMed ID: 31019026). Functional studies found this variant retains ~80% of normal NODAL activity (Roessler et al. 2009. PubMed ID: 19553149). However, this variant has also been reported in 0.22% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-72195155-C-T) and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/8269/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Likely benign
(Nov 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Heterotaxy, visceral, 5, autosomal
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000652387.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
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Pathogenic
(Mar 01, 2009)
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no assertion criteria provided
Method: literature only
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HETEROTAXY, VISCERAL, 5, AUTOSOMAL
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028967.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 27, 2019 |
Comment on evidence:
In 8 of 82 unrelated Hispanic patients with heterotaxy (HTX5; 270100), Mohapatra et al. (2009) identified a heterozygous 778G-A transition in exon 2 of the … (more)
In 8 of 82 unrelated Hispanic patients with heterotaxy (HTX5; 270100), Mohapatra et al. (2009) identified a heterozygous 778G-A transition in exon 2 of the NODAL gene, resulting in a gly260-to-arg (G260R) substitution in a highly conserved residue. Most patients had d-transposition of the great arteries in addition to other cardiac anomalies, 3 had abdominal situs inversus, and 2 had asplenia. The detection of this variant in the unaffected father of 1 patient and 1 of 108 Hispanic controls, suggested incomplete penetrance. None of the 190 Caucasian or African American controls examined carried the variant. Functional analysis showed reduced NODAL signaling through both FOXH1-dependent and -independent pathways, as well as reduced SMAD2 phosphorylation and impaired nuclear import. (less)
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Pathogenic
(Jul 14, 2017)
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no assertion criteria provided
Method: research
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Wolff-Parkinson-White pattern
Affected status: yes
Allele origin:
inherited
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Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Study: Candidate_variants_in_patients_with_ Wolff-Parkinson-White Syndrome
Accession: SCV000678363.1 First in ClinVar: Jun 02, 2018 Last updated: Jun 02, 2018 |
Comment:
This variant was identified in an individual with Wolff-Parkinson-White syndrome
Number of individuals with the variant: 1
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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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Identification and functional characterization of NODAL rare variants in heterotaxy and isolated cardiovascular malformations. | Mohapatra B | Human molecular genetics | 2009 | PMID: 19064609 |
Text-mined citations for rs121909283 ...
HelpRecord last updated Apr 20, 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.