Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001843352 | SCV002102554 | likely benign | Glaucoma of childhood | 2022-03-05 | reviewed by expert panel | curation | The c.144G>T variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 48 (p.Gln48His). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.007937, which met the >= 0.001 threshold set for BS1 (243 alleles out of 30,616, meeting the threshold of >= 5 of at least 2,000 observed alleles). The REVEL score = 0.257, which was neither above nor below the thresholds for PP3 (>= 0.7) or BP4 (<= 0.15), predicting a damaging or benign impact on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Gln48His protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of - 6 and to be classified as likely benign (likely benign classification range - 2 to - 6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BS3_Moderate. |
| Illumina Laboratory Services, |
RCV000296614 | SCV000351312 | pathogenic | MYOC-related disorder | 2017-08-30 | criteria provided, single submitter | clinical testing | Across a selection of the available literature, the MYOC c.144G>T (p.Gln48His) missense variant has been identified in a homozygous state in one individual with primary congenital glaucoma (PCG), and in a heterozygous state in 13 individuals with primary open angle glaucoma, eight with PCG, four with juvenile open angle glaucoma and five with microcoria and glaucoma (Mukhopadhyay et al. 2002; Sripriya et al. 2004; Chakrabarti et al. 2005; Kaur et al. 2005; Ramprasad et al. 2005; Kumar et al. 2007; Rose et al. 2011; Banerjee et al. 2012). The variant was absent from 1110 ethnically matched controls but is reported with a frequency of 0.02451 in the Sri Lankan Tamil in the UK population of the 1000 Genomes Project. This allele frequency is high but is consistent with the variant being one of the most commonly reported and well-described variants associated with glaucoma in the South Asian population (Sripriya et al. 2004; Ramprasad et al. 2005). The Gln48 residue is conserved. Based on the collective evidence, the p.Gln48His variant is classified as pathogenic for MYOC-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Invitae | RCV001520657 | SCV001729816 | benign | not provided | 2023-02-02 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV000008421 | SCV002798955 | likely benign | Glaucoma 1, open angle, A | 2022-05-17 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV000296614 | SCV004772210 | likely benign | MYOC-related disorder | 2022-08-24 | criteria provided, single submitter | clinical testing | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). |
| OMIM | RCV000008421 | SCV000028629 | pathogenic | Glaucoma 1, open angle, A | 2005-04-01 | no assertion criteria provided | literature only | |
| OMIM | RCV000008422 | SCV000028630 | pathogenic | Glaucoma 3, primary congenital, a, digenic | 2005-04-01 | no assertion criteria provided | literature only | |
| Reproductive Health Research and Development, |
RCV000008421 | SCV001142312 | pathogenic | Glaucoma 1, open angle, A | 2020-01-06 | no assertion criteria provided | curation | NM_000261.1:c.144G>T in the MYOC gene has an allele frequency of 0.008 in South Asian subpopulation in the gnomAD database.The MYOC c.144G>T (p.Gln48His) missense variant was identified in 4 of the 450 POAG patients (PMID: 22736945) and in two POAG patients from Chennai (PMID: 22194650). It was also observed in five of the eight glaucoma patients (PMID: 16288197). Chakrabarti S et al reported that the Gln48His mutation was detected in 9 different glaucoma patients (four POAG and five PCG) and all four POAG cases were heterozygous, among PCG cases, four were heterozygous and one exhibited homozygous genotype for the mutation(PMID: 15723004). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3, PS4, PP4 |