Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genetic Services Laboratory, |
RCV000500415 | SCV000597527 | pathogenic | Congenital myopathy 23 | 2016-04-28 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000532873 | SCV000630170 | pathogenic | Arthrogryposis, distal, type 1A | 2020-03-04 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this in-frame deletion causes increased calcium sensitivity and inhibits myosin binding (PMID: 23886664, 25978979). This variant has been reported in multiple unrelated individuals affected with autosomal dominant cap myopathy and nemaline myopathy (PMID: 17434307, 23015096, 24692096, 25127990), including several affected individuals where it arose de novo (PMID: 19345583, 24507666). ClinVar contains an entry for this variant (Variation ID: 12465). This variant is not present in population databases (ExAC no frequency). This variant, c.415_417del, results in the deletion of 1 amino acid of the TPM2 protein (p.Glu139del), but otherwise preserves the integrity of the reading frame. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000500415 | SCV002511663 | pathogenic | Congenital myopathy 23 | 2022-04-07 | criteria provided, single submitter | clinical testing | Variant summary: TPM2 c.415_417delGAG (p.Glu139del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 251480 control chromosomes. c.415_417delGAG has been reported in the literature in multiple individuals affected with Nemaline Myopathy 4 (Cap myopathy) (example, Lehtokari_2007, Clarke_2009, Tasca_2013, Citirak_2014). Some of the ascertained reports indicated a de-novo origin and at-least once instance of somatic mosaicism resulting in a milder presentation has been reported (example, Tasca_2013). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence that the mutant protein incorporates into sarcomeric structures, where it likely imposes a dominant-negative effect to cause muscle weakness (example, Clarke_2009) and increased myofibrillar calcium sensitivity consistent with a gain of function mechanism (example, Marston_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
MGZ Medical Genetics Center | RCV000500415 | SCV002581247 | pathogenic | Congenital myopathy 23 | 2021-11-04 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000128684 | SCV003917658 | pathogenic | not provided | 2023-02-01 | criteria provided, single submitter | clinical testing | TPM2: PS2, PM2, PS3:Moderate, PS4:Moderate |
Prevention |
RCV004528107 | SCV004109058 | pathogenic | TPM2-related disorder | 2024-02-15 | criteria provided, single submitter | clinical testing | The TPM2 c.415_417delGAG variant is predicted to result in an in-frame deletion (p.Glu139del). This variant was reported in numerous individuals with nemaline myopathy or CAP myopathy (Lehtokari et al. 2007. PubMed ID: 17434307; Marttila et al. 2014. PubMed ID: 24692096; Table S1, Westra et al. 2019. PubMed ID: 31127727; Supplementary data, Gonzalez-Quereda et al. 2020. PubMed ID: 32403337). Functional studies showed that this variant impacts normal protein function (Marttila et al. 2012. PubMed ID: 22084935; Marston et al. 2013. PubMed ID: 23886664; Borovikov et al. 2015. PubMed ID: 25978979). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. |
OMIM | RCV000500415 | SCV000033528 | pathogenic | Congenital myopathy 23 | 2009-05-01 | no assertion criteria provided | literature only | |
TPM2 homepage - |
RCV000128684 | SCV000172324 | not provided | not provided | no assertion provided | not provided |