Submissions for variant NM_006206.6(PDGFRA):c.1325T>C (p.Leu442Pro)

gnomAD frequency: 0.00064  dbSNP: rs139236922

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001082697	SCV000289157	likely benign	Gastrointestinal stromal tumor	2024-02-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764538	SCV000895624	uncertain significance	Gastrointestinal stromal tumor; Idiopathic hypereosinophilic syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001011041	SCV001171319	uncertain significance	Hereditary cancer-predisposing syndrome	2018-09-19	criteria provided, single submitter	clinical testing	The p.L442P variant (also known as c.1325T>C), located in coding exon 8 of the PDGFRA gene, results from a T to C substitution at nucleotide position 1325. The leucine at codon 442 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034715	SCV002009617	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001011041	SCV002538546	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-22	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003398593	SCV004102999	uncertain significance	PDGFRA-related condition	2022-08-31	criteria provided, single submitter	clinical testing	The PDGFRA c.1325T>C variant is predicted to result in the amino acid substitution p.Leu442Pro. This variant has not been reported in association with a hereditary cancer phenotype; however, it was identified in a cohort of individuals ascertained for atherosclerosis (Table S1, Johnston et al. 2012. PubMed ID: 22703879). This variant is reported in 0.079% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-55138648-T-C) and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/41793). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Revvity Omics, Revvity	RCV003485527	SCV004235740	uncertain significance	Idiopathic hypereosinophilic syndrome	2023-06-09	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034715	SCV000043406	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000034715	SCV001552050	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PDGFRA p.Leu455Pro variant was not identified in the literature but was identified in dbSNP (ID: rs139236922) and ClinVar (classified as uncertain significance by Fulgent Genetics, Ambry Genetics and Biesecker Lab/Clinical Genomics Section, National Institutes of Health, and as likely benign by Invitae). The variant was identified in control databases in 133 of 268128 chromosomes at a frequency of 0.000496 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: European (non-Finnish) in 97 of 118008 chromosomes (freq: 0.000822), Latino in 18 of 35102 chromosomes (freq: 0.000513), Other in 3 of 6694 chromosomes (freq: 0.000448), South Asian in 11 of 30526 chromosomes (freq: 0.00036), African in 3 of 23608 chromosomes (freq: 0.000127) and European (Finnish) in 1 of 25092 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Leu455 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this is not very predictive of 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.