Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001843351 | SCV002102548 | pathogenic | Glaucoma of childhood | 2022-03-05 | reviewed by expert panel | curation | The c.1102C>T variant in MYOC is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Glutamine at amino acid 368 (p.Gln368Ter). This variant is predicted to cause a deletion of >= 10% of the protein within the conserved olfactomedin domain, meeting PM4. Although this variant had a minor allele frequency of 0.003344 in the European (Finnish) population of gnomAD (84 alleles out of 25,118), which meets the >= 0.001 threshold for BS1, Gln368Ter is exempt from this criterion due to its incomplete penetrance and the presence of a common disease haplotype in all carriers. There was no computational evidence predicting a damaging or benign impact of this variant on MYOC function. This variant is exempt from the rule which normally does not allow the application of PS4 unless PM2_Supporting is met. 23 probands with juvenile or primary open angle glaucoma (JOAG or POAG) have been reported carrying this variant (PMIDs: 11535458, 11004290, 10815160, 22736945, 11803488, 12189160), which met PS4 (>= 15 probands). As this variant is exempt from the application of BS1, PP1 has been applied. 52 segregations in 10 families, with JOAG or POAG, have been reported (PMIDs: 11004290, 10815160, 11535458), which fulfilled PP1_Strong (>= 7 meioses in > 1 family). There were many more probands and family studies published than presented here. A previous study (PMID: 16466712) demonstrated that the Gln368Ter protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. In summary, this variant met the criteria to receive a score of 12 and to be classified as pathogenic (pathogenic classification >= 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PM4, PS3_Moderate. |
Illumina Laboratory Services, |
RCV000369379 | SCV000351279 | likely pathogenic | Primary open angle glaucoma | 2016-06-14 | criteria provided, single submitter | clinical testing | The c.1102C>T (p.Gln368Ter) variant is a stop-gained variant. Across a selection of the available literature, the p.Gln368Ter variant has been identified in a heterozygous state in 107 patients affected with primary open angle glaucoma (POAG) or ocular hypertension (Stone et al. 1997; Angius et al. 2000; Craig et al. 2001; Mataftsi et al. 2001; Cobb et al. 2002; Faucher et al. 2002; Melki et al. 2003; Bhattacharjee et al. 2007; Lopez-Martinez et al. 2007; Hogewind et al. 2010; Liu et al. 2012; Young et al. 2012). The p.Gln368Ter variant was also reported in a heterozygous state in 56 controls and unaffected family members and is reported at a frequency of 0.00363 in the European (Finnish) population of the Exome Aggregation Consortium. The relatively high number of unaffected individuals carrying the variant could be consistent with reduced or age-related penetrance. This variant may represent a risk allele for development of POAG. In vitro functional studies by Aroca-Aquilar et al. (2008) showed that heterozygous expression of the p.Gln368Ter variant increases secretion of the variant protein and reduces extracellular processed myocilin, while Qiu et al. (2014) demonstrated that p.Gln368Ter variant myocilin results in compromised ubiquitin-proteasome function and induced autophagy. Based on the evidence, the p.Gln368Ter variant is classified as likely pathogenic and possible risk allele for primary open angle glaucoma. |
Center for Personalized Medicine, |
RCV000735309 | SCV000854462 | likely pathogenic | Severe combined immunodeficiency disease; Immunodeficiency; Lymphopenia; Abnormal cellular immune system morphology; Abnormality of T cell physiology; Combined immunodeficiency | criteria provided, single submitter | clinical testing | ||
Centre for Mendelian Genomics, |
RCV000008412 | SCV001370031 | likely pathogenic | Glaucoma 1, open angle, A | 2016-01-01 | criteria provided, single submitter | clinical testing | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM1,PP5. |
Ce |
RCV001200372 | SCV001371312 | pathogenic | not provided | 2024-02-01 | criteria provided, single submitter | clinical testing | MYOC: PP1:Strong, PVS1:Strong, PS3:Moderate, PS4:Moderate |
Mendelics | RCV000008412 | SCV002517760 | pathogenic | Glaucoma 1, open angle, A | 2022-05-04 | criteria provided, single submitter | clinical testing | |
Pars Genome Lab | RCV000008412 | SCV002549910 | likely benign | Glaucoma 1, open angle, A | criteria provided, single submitter | clinical testing | ||
Genetics and Molecular Pathology, |
RCV000008412 | SCV002556926 | pathogenic | Glaucoma 1, open angle, A | 2020-04-02 | criteria provided, single submitter | clinical testing | |
Gene |
RCV001200372 | SCV002562489 | pathogenic | not provided | 2023-04-18 | criteria provided, single submitter | clinical testing | Reported as the most common pathogenic variant in association with MYOC-related primary open-angle glaucoma (Stone et al., 1997; Milla et al., 2013; Nag et al., 2017); Published functional studies demonstrate a damaging effect with suppression of normal myocilin secretion and intracellular sequestration (Jacobson et al., 2001; Gobeil et al., 2006); Nonsense variant predicted to result in protein truncation, as the last 137 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 26396484, 10209734, 26237198, 33713785, 34662886, 23922489, 23304066, 22615763, 23029558, 9005853, 27993484, 28282485, 19023451, 16466712, 11535458, 30267046, 30816137, 30484747, 30816940, 34426522, 34081096, 31589614, 30755392, 32476818, 11803488, 16358725, 34082484, 28038983, 11152659) |
Invitae | RCV001200372 | SCV003256865 | pathogenic | not provided | 2024-01-08 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln368*) in the MYOC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 137 amino acid(s) of the MYOC protein. This variant is present in population databases (rs74315329, gnomAD 0.4%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with primary open angle glaucoma, with reduced penetrance and variable age of onset (PMID: 10815160, 11004290, 23029558). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7949). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MYOC function (PMID: 19023451, 26396484). For these reasons, this variant has been classified as Pathogenic. |
Baylor Genetics | RCV000008412 | SCV003835338 | pathogenic | Glaucoma 1, open angle, A | 2022-11-02 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000008412 | SCV000028620 | pathogenic | Glaucoma 1, open angle, A | 2003-02-01 | no assertion criteria provided | literature only |