ClinVar Miner

Submissions for variant NM_018055.5(NODAL):c.778G>A (p.Gly260Arg)

gnomAD frequency: 0.00004  dbSNP: rs121909283
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000008758 SCV000652387 likely benign Heterotaxy, visceral, 5, autosomal 2025-02-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622859 SCV000740871 likely pathogenic Inborn genetic diseases 2015-04-03 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001824117 SCV000996070 likely pathogenic Visceral heterotaxy 2017-08-29 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV000008758 SCV001520332 uncertain significance Heterotaxy, visceral, 5, autosomal 2021-12-15 criteria provided, single submitter clinical testing
Genomic Medicine Lab, University of California San Francisco RCV000008758 SCV001573085 uncertain significance Heterotaxy, visceral, 5, autosomal 2021-01-07 criteria provided, single submitter clinical testing
GeneDx RCV001558244 SCV001780150 uncertain significance not provided 2023-03-16 criteria provided, single submitter clinical testing 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)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000008758 SCV002050203 uncertain significance Heterotaxy, visceral, 5, autosomal 2021-01-20 criteria provided, single submitter clinical testing 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.
PreventionGenetics, part of Exact Sciences RCV004528096 SCV004105165 uncertain significance NODAL-related disorder 2023-07-31 criteria provided, single submitter clinical testing 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.
Juno Genomics, Hangzhou Juno Genomics, Inc RCV000008758 SCV005416089 likely pathogenic Heterotaxy, visceral, 5, autosomal criteria provided, single submitter clinical testing PM2_Supporting+PP3_Moderate+PS2_Supporting+PS4_Moderate+PP4
OMIM RCV000008758 SCV000028967 pathogenic Heterotaxy, visceral, 5, autosomal 2009-03-01 no assertion criteria provided literature only
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656169 SCV000678363 pathogenic Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome

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