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

gnomAD frequency: 0.00004  dbSNP: rs121909283

Total submissions: 11

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