ClinVar Miner

Submissions for variant NM_006206.6(PDGFRA):c.1133A>T (p.Lys378Ile)

gnomAD frequency: 0.00003  dbSNP: rs200113704
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000206492 SCV000261667 uncertain significance Gastrointestinal stromal tumor 2024-01-10 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 378 of the PDGFRA protein (p.Lys378Ile). This variant is present in population databases (rs200113704, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PDGFRA-related conditions. ClinVar contains an entry for this variant (Variation ID: 220810). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PDGFRA protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV001009956 SCV001170090 benign Hereditary cancer-predisposing syndrome 2024-08-20 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences RCV003417749 SCV004108473 uncertain significance PDGFRA-related disorder 2023-03-10 criteria provided, single submitter clinical testing The PDGFRA c.1133A>T variant is predicted to result in the amino acid substitution p.Lys378Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-55136811-A-T) and interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/220810/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics RCV004567481 SCV005055145 uncertain significance Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal 2024-03-07 criteria provided, single submitter clinical testing
GeneDx RCV004589898 SCV005080954 uncertain significance not provided 2023-10-03 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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