Submissions for variant NM_005373.3(MPL):c.1102G>T (p.Val368Leu)

gnomAD frequency: 0.00039  dbSNP: rs149810307

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000400513	SCV000357772	likely benign	Thrombocythemia 1	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000315154	SCV000357773	likely benign	Congenital amegakaryocytic thrombocytopenia	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000315154	SCV000792168	uncertain significance	Congenital amegakaryocytic thrombocytopenia	2017-06-16	criteria provided, single submitter	clinical testing
Invitae	RCV001246816	SCV001420202	uncertain significance	Congenital amegakaryocytic thrombocytopenia; Essential thrombocythemia	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 368 of the MPL protein (p.Val368Leu). This variant is present in population databases (rs149810307, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with MPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 134839). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Genetic Services Laboratory, University of Chicago	RCV000121554	SCV002069491	uncertain significance	not specified	2020-07-28	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MPL gene demonstrated a sequence change, c.1102G>T, in exon 7 that results in an amino acid change, p.Val368Leu. This sequence change does not appear to have been previously described in patients with MPL-related disorders and has been described in the gnomAD database with a relatively high population frequency of 0.078% in the non-Finnish European subpopulation (dbSNP rs149810307). The p.Val368Leu change affects a moderately conserved amino acid residue located in a domain of the MPL protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val368Leu substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val368Leu change remains unknown at this time
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121554	SCV004242093	uncertain significance	not specified	2023-12-01	criteria provided, single submitter	clinical testing	Variant summary: MPL c.1102G>T (p.Val368Leu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 251490 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MPL causing Congenital Amegakaryocytic Thrombocytopenia (0.0004 vs 0.0024), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1102G>T in individuals affected with Congenital Amegakaryocytic Thrombocytopenia and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS=4; Likely benign=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
ITMI	RCV000121554	SCV000085748	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358413	SCV001554138	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MPL p.Val368Leu variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs149810307) and ClinVar (classified as likely benign by Illumina and uncertain significance by Counsyl). The variant was identified in control databases in 109 of 268334 chromosomes at a frequency of 0.0004062 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 93 of 118170 chromosomes (freq: 0.000787), Other in 4 of 6708 chromosomes (freq: 0.000596), African in 5 of 23602 chromosomes (freq: 0.000212), Latino in 6 of 35106 chromosomes (freq: 0.000171) and South Asian in 1 of 30526 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The p.Val368 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 three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. 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.
Natera, Inc.	RCV000315154	SCV002086032	uncertain significance	Congenital amegakaryocytic thrombocytopenia	2020-04-03	no assertion criteria provided	clinical testing