ClinVar Genomic variation as it relates to human health

This nonsense variant is found in the last exon of GDF1 and is therefore predicted to escape nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in an individual with transposition of the great arteries (PMID: 17924340), and as a compound heterozygous change in patients with cardiac defects (PMID: 20413652, 28991257), including five siblings with right atrial isomerism, who harbored a frameshift variant on the opposite GDF1 allele; the parent who was heterozygous for the p.Cys227Ter variant was unaffected (PMID: 20413652). Heterozygous loss-of-function mutations in GDF1 are a known mechanism of cardiac defects ranging from tetralogy of Fallot to transposition of the great arteries (PMID: 17924340, 28991257, 23410880). The c.681C>A (p.Cys227Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.05% (13/25686) and thus is presumed to be rare. Based on the available evidence, the c.681C>A (p.Cys227Ter) variant is classified as Likely Pathogenic.

This sequence change creates a premature translational stop signal (p.Cys227*) in the GDF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 146 amino acid(s) of the GDF1 protein. This variant is present in population databases (rs121434422, gnomAD 0.09%). This premature translational stop signal has been observed in individual(s) with heterotaxy syndrome (PMID: 20413652). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6747). This variant disrupts the p.Cys277 amino acid residue in GDF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17924340, 17936261, 20413652). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 5-pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with right atrial isomerism (MIM#208530). Although loss of function has been demonstrated for missense variants, there is currently limited evidence demonstrating loss of function for truncating variants (PMIDs: 1792434; 20413652). (I) 0106 - This gene is associated with autosomal recessive disease. This gene has also been associated right atrial isomerism (Ivemark) (RAI) (MIM#208530) and congenital heart defects, multiple types, 6 (MIM#613854) (OMIM; PMID: 28991257) (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. This variant might also affect the production of active protein although there is currently no functional evidence demonstrating this (PMID: 1792434; 20413652). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0702 - Other protein truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity. There are two protein truncating variants downstream of our variant of interest (ClinVar, Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in 4 unrelated individuals with right atrial isomerism (MIM#208530) and a single patient with congenital heart defect (MIM#613854) (ClinVar, PMIDs: 1792434, 20413652, 32144877). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in one family with five individuals diagnosed with right atrial isomerism (MIM#208530) (PMID: 20413652). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual's fetus. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.1047_1050delCTTT; p.(Phe349Leufs*35)) in a recessive disease (reported by Invitae #RQ1502139). (SP) 1205 - This variant has been shown to be paternally inherited in the fetus with symptoms consistent with congenital heart defects or heterotaxy (reported by Invitae #RQ1502139). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Nonsense variant predicted to result in protein truncation, as the last 146 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 29429572, 32144877, 30679813, 34313030, 26258520, 18375573, 20497191, 19553149, 14648004, 20413652, 28991257, 34328347, 17924340)

GDF1: PVS1:Strong, PM1, PM2, PM3

The GDF1 c.681C>A variant is predicted to result in premature protein termination (p.Cys227*). This variant has previously been reported in the heterozygous state in an individual with transposition of the great arteries (Kakera et al. 2007. PubMed ID: 17924340). This variant was also reported in an individual with conotruncal defects. The variant was inherited; however, the phenotype of the parents was not provided (Patient 1-05514 - Table S1/S7 - Jin et al. 2017. PubMed ID: 28991257). In the compound heterozygous state this variant was found in five siblings with right atrial isomerism (Kaasinen et al. 2010. PubMed ID: 20413652) and an individual with heterotaxy (Patient 1-05386 - Table S1/S3 - Jin et al. 2017. PubMed ID: 28991257). The parents of the five siblings with right atrial isomerism were reported to be unaffected (Kaasinen et al. 2010. PubMed ID: 20413652). Of note, this variant is in 13 out of 25,686 alleles (~0.05%) in the gnomAD database; however, this may not be accurate due to low sequence coverage in this region. Nonsense variants in GDF1 are expected to be pathogenic for autosomal recessive disease; however, their role in autosomal dominant disease is uncertain. This variant is interpreted as pathogenic.