Total submissions: 11
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
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, |
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, |
RCV000008758 | SCV001573085 | uncertain significance | Heterotaxy, visceral, 5, autosomal | 2021-01-07 | criteria provided, single submitter | clinical testing | |
Gene |
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, |
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. |
Prevention |
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, |
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, |
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 |