rs74315329
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP1_StrongPS4PM4PS3_Moderate
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA119172/MONDO:0020367/019
Frequency
Consequence
NM_000261.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYOC | NM_000261.2 | c.1102C>T | p.Gln368Ter | stop_gained | 3/3 | ENST00000037502.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYOC | ENST00000037502.11 | c.1102C>T | p.Gln368Ter | stop_gained | 3/3 | 1 | NM_000261.2 | P1 | |
MYOCOS | ENST00000637303.1 | c.235-2292G>A | intron_variant | 5 | A2 | ||||
MYOC | ENST00000638471.1 | c.*440C>T | 3_prime_UTR_variant, NMD_transcript_variant | 4/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000849 AC: 129AN: 152014Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00111 AC: 279AN: 251404Hom.: 0 AF XY: 0.00119 AC XY: 162AN XY: 135874
GnomAD4 exome AF: 0.00119 AC: 1741AN: 1461842Hom.: 1 Cov.: 31 AF XY: 0.00118 AC XY: 859AN XY: 727232
GnomAD4 genome ? AF: 0.000848 AC: 129AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.000807 AC XY: 60AN XY: 74370
ClinVar
Submissions by phenotype
Glaucoma 1, open angle, A Pathogenic:6Benign:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 02, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Pars Genome Lab | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM1,PP5. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 16, 2023 | 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 - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2003 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 02, 2020 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | MYOC: PP1:Strong, PVS1:Strong, PS3:Moderate, PS4:Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2023 | 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) - |
Immunodeficiency;C0024312:Lymphopenia;C0085110:Severe combined immunodeficiency disease;C2711630:Combined immunodeficiency;C4023166:Abnormality of T cell physiology;C4023612:Abnormal cellular immune system morphology Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Personalized Medicine, Children's Hospital Los Angeles | - | - - |
Glaucoma of childhood Pathogenic:1
Pathogenic, reviewed by expert panel | curation | ClinGen Glaucoma Variant Curation Expert Panel | Mar 05, 2022 | 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. - |
Primary open angle glaucoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at