Submissions for variant NM_000261.2(MYOC):c.1102C>T (p.Gln368Ter)

gnomAD frequency: 0.00089  dbSNP: rs74315329

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Glaucoma Variant Curation Expert Panel	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, Illumina	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, Children's Hospital Los Angeles	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, University Medical Centre Ljubljana	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.
CeGaT Center for Human Genetics Tuebingen	RCV001200372	SCV001371312	pathogenic	not provided	2024-08-01	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, SA Pathology	RCV000008412	SCV002556926	pathogenic	Glaucoma 1, open angle, A	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001200372	SCV002562489	pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	Reported as the most common pathogenic variant in association with MYOC-related primary open-angle glaucoma (PMID: 28038983, 23922489, 9005853); Published functional studies demonstrate a damaging effect with suppression of normal myocilin secretion and intracellular sequestration (PMID: 11152659, 16466712); 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, 36217948, 36450729, 11152659, 28038983)
Labcorp Genetics (formerly Invitae), Labcorp	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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000008412	SCV005086755	pathogenic	Glaucoma 1, open angle, A	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with glaucoma 1A, primary open angle (MIM#137750). Functional studies have shown that pathogenic MYOC variants cause the protein to be processed incorrectly by the endoplasmic reticulum, causing the accumulation of insoluble aggregates and apoptosis via the unfolded protein response (PMID: 15069026). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (314 heterozygotes, 0 homozygotes). (I) 0600 - Variant truncates the annotated olfactomedin-like domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel in ClinVar and has been observed in many individuals with glaucoma. Studies have shown that 48% of carriers of this variant over the age of 65 develop glaucoma or ocular hypertension (PMID: 30267046). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000008412	SCV000028620	pathogenic	Glaucoma 1, open angle, A	2003-02-01	no assertion criteria provided	literature only