Submissions for variant NM_016204.4(GDF2):c.871G>A (p.Gly291Ser)

gnomAD frequency: 0.00045  dbSNP: rs201711410

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000757326	SCV000532993	uncertain significance	not provided	2016-10-26	criteria provided, single submitter	clinical testing	The G291S variant in the GDF2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G291S variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G291S variant is a non-conservative amino acid substitution, which occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret G291S as a variant of uncertain significance,
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757326	SCV000885505	uncertain significance	not provided	2018-05-15	criteria provided, single submitter	clinical testing	The GDF2 c.871G>A; p.Gly291Ser variant (rs201711410), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 390215). This variant is found in the general population with an overall allele frequency of 0.007% (20/277208 alleles) in the Genome Aggregation Database. The glycine at codon 291 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Gly291Ser variant is uncertain at this time.
Invitae	RCV000813163	SCV000953508	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 5	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 291 of the GDF2 protein (p.Gly291Ser). This variant is present in population databases (rs201711410, gnomAD 0.03%). This missense change has been observed in individual(s) with pulmonary arterial malformations, pulmonary arterial hypertension or hypertrophic cardiomyopathy (PMID: 31661308, 32992168). ClinVar contains an entry for this variant (Variation ID: 390215). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000813163	SCV002815048	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 5	2022-02-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000757326	SCV004127633	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	GDF2: BS2
PreventionGenetics, part of Exact Sciences	RCV003970221	SCV004785891	uncertain significance	GDF2-related condition	2024-02-02	criteria provided, single submitter	clinical testing	The GDF2 c.871G>A variant is predicted to result in the amino acid substitution p.Gly291Ser. This variant was reported in an individual with pulmonary arteriovenous malformations (Topiwala et al. 2020. PubMed ID: 32992168). This variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000757326	SCV001550935	uncertain significance	not provided		no assertion criteria provided	clinical testing	The GDF2 p.Gly291Ser variant was identified in the literature in a case of idiopathic and heritable pulmonary arterial hypertension and a case of hypertrophic cardiomyopathy but suggested to be benign (Hodgson_2020_PMID:31661308). The variant was identified in dbSNP (ID: rs201711410) and ClinVar (classified as uncertain significance by Invitae, GeneDx and ARUP laboratories). The variant was identified in control databases in 20 of 282818 chromosomes at a frequency of 0.00007072 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 11 of 35434 chromosomes (freq: 0.00031), Other in 2 of 7226 chromosomes (freq: 0.000277), South Asian in 2 of 30616 chromosomes (freq: 0.000065), African in 1 of 24962 chromosomes (freq: 0.00004) and European (non-Finnish) in 4 of 129146 chromosomes (freq: 0.000031), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Gly291 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.