ClinVar Miner

Submissions for variant NM_001366145.2(TRPM3):c.3004G>A (p.Val1002Met) (rs1564493599)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000709842 SCV001155652 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing
Laboratoire de Genetique Moleculaire,Centre Hospitalier Universitaire de Bordeaux RCV001199967 SCV001161767 likely pathogenic Intellectual disability 2019-07-12 criteria provided, single submitter clinical testing This missense has been reported in 7 individuals as de novo causing variation (deleterious predicted effects + absent from control database) for a new autosomal dominant form of intellectual disability and epilepsy by Dyment et al. 2019, EJHG. The phenotypic concordance with a independent previous description of the same missense along with its in-silico deleterious predicted effect and its absence from controls meet our criteria to be classified as pathogenic.
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV001199967 SCV001434329 pathogenic Intellectual disability 2020-09-30 criteria provided, single submitter clinical testing Recurrent variant in the litterature. De novo. 20A2340
GenomeConnect, ClinGen RCV000709842 SCV000840172 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pediatrics,University of Ottawa RCV000766226 SCV000891785 pathogenic Global developmental delay; Seizures 2019-03-26 no assertion criteria provided clinical testing Identified de novo in each of six individuals with epilepsy and developmental delay by whole-exome trio sequencing.
OMIM RCV000709842 SCV001146963 uncertain significance not provided 2020-02-11 no assertion criteria provided literature only
Broad Institute Rare Disease Group, Broad Institute RCV001267689 SCV001445934 pathogenic Mulibrey nanism syndrome 2020-11-16 no assertion criteria provided curation The heterozygous p.Val1002Met (Val837Met) variant in TRPM3 was identified by our study in 1 individual with intellectual disability and epilepsy, and also mulibrey nanism caused by 2 variants in the compound heterozygous state in TRIM37. Trio genome analysis showed this variant to be de novo. The variant has been reported in 7 individuals with intellectual disability and epilepsy (PMID: 31278393), and was absent from large population studies. This variant was found to be de novo in all 7 individuals with confirmed paternity and maternity (PMID: 31278393), and has also been reported in ClinVar (Variation ID: 585073) and interpreted as pathogenic by department of pediatrics, University of Ottawa, and as uncertain significance by OMIM, and CeGaT Praxis fuer Humangenetik Tuebingen. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in TRPM3 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant intellectual disability and epilepsy. ACMG/AMP Criteria applied: PS2_verystrong, PM2, PS4_moderate, PP2, PP3 (Richards 2015).

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