ClinVar Miner

Submissions for variant NM_005373.3(MPL):c.684T>A (p.Ser228Arg)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV004787084 SCV005402190 uncertain significance Thrombocythemia 2 2023-11-28 criteria provided, single submitter clinical testing The MPL c.684T>A (p.Ser228Arg) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with MPL-associated disorders. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ambry Genetics RCV004950767 SCV005450536 uncertain significance Inborn genetic diseases 2024-09-10 criteria provided, single submitter clinical testing The c.684T>A (p.S228R) alteration is located in exon 4 (coding exon 4) of the MPL gene. This alteration results from a T to A substitution at nucleotide position 684, causing the serine (S) at amino acid position 228 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV005220804 SCV005868794 uncertain significance Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia 2024-04-30 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 228 of the MPL protein (p.Ser228Arg). This variant is present in population databases (rs766536759, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MPL-related conditions. 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 MPL protein function with a negative predictive value of 95%. 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.
PreventionGenetics, part of Exact Sciences RCV004544015 SCV004758829 uncertain significance MPL-related disorder 2023-11-27 no assertion criteria provided clinical testing The MPL c.684T>A variant is predicted to result in the amino acid substitution p.Ser228Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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