VCV000007949.50 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

13 submissions

13 submitters

5 conditions

Reviewed by expert panel

Pathogenic

Mar 2022 by ClinGen Glauco… FDA Recognized Database

for Glaucoma of childhood

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 7949 Accession: VCV000007949.50

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q24.3 1: 171636338 (GRCh38) [ NCBI UCSC ] 1: 171605478 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Oct 20, 2024	Mar 5, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000261.2:c.1102C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000252.1:p.Gln368Ter	nonsense
NC_000001.11:g.171636338G>A
NC_000001.10:g.171605478G>A
NG_008859.1:g.21296C>T

Protein change

Q368*

Other names

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

Canonical SPDI

NC_000001.11:171636337:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00060 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00047

1000 Genomes Project 0.00060

Trans-Omics for Precision Medicine (TOPMed) 0.00072

The Genome Aggregation Database (gnomAD) 0.00089

Exome Aggregation Consortium (ExAC) 0.00109

The Genome Aggregation Database (gnomAD), exomes 0.00111

Links

ClinGen: CA119172 OMIM: 601652.0003 dbSNP: rs74315329 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MYOC		-	-	GRCh38 GRCh37	317	345

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Primary open angle glaucoma	Likely pathogenic (1)	criteria provided, single submitter	Jun 14, 2016	RCV000369379.7
Glaucoma 1, open angle, A	Conflicting interpretations of pathogenicity (7)	criteria provided, conflicting classifications	Jul 16, 2023	RCV000008412.16
Abnormal cellular immune system morphology Abnormality of T cell physiology Combined immunodeficiency Immunodeficiency Lymphopenia Severe combined immunodeficiency disease	Likely pathogenic (1)	criteria provided, single submitter	-	RCV000735309.4
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV001200372.28
Glaucoma of childhood	Pathogenic (1)	reviewed by expert panel	Mar 5, 2022	RCV001843351.5

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 05, 2022)	reviewed by expert panel (ClinGen Glaucoma ACMG Specifications v1.1) Method: curation	Glaucoma of childhood (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Glaucoma Variant Curation Expert Panel FDA Recognized Database Accession: SCV002102548.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Publications: PubMed (1) PubMed: 11004290 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/399db6af-6807-459a-9953-39c259125cad Comment: 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 … (more) 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. (less)
Likely pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glaucoma 1, open angle, A Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001370031.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM1,PP5.
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Glaucoma 1, open angle, A Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002517760.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Apr 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glaucoma 1, open angle, A Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556926.2 First in ClinVar: Aug 04, 2022 Last updated: Dec 17, 2022
Pathogenic (Jan 08, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003256865.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 10815160‚ 11004290‚ 23029558‚ 19023451‚ 26396484 Comment: 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, … (more) 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. (less)
Pathogenic (Dec 11, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002562489.4 First in ClinVar: Aug 23, 2022 Last updated: Jul 23, 2024	Comment: 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 … (more) 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) (less)
Likely pathogenic (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Primary Open Angle Glaucoma Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000351279.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (15) PubMed: 9005853‚ 9639450‚ 10815160‚ 11535458‚ 11803488‚ 11815346‚ 12189160‚ 12872267‚ 17562996‚ 17615537‚ 20021252‚ 22933836‚ 23304066‚ 19023451‚ 24732711 Comment: 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 … (more) 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. (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Abnormal cellular immune system morphology Combined immunodeficiency Immunodeficiency Lymphopenia Abnormality of T cell physiology Severe combined immunodeficiency disease Affected status: yes Allele origin: germline	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV000854462.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Sex: female
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glaucoma 1, open angle, A (Autosomal dominant inheritance) Affected status: no Allele origin: germline	Pars Genome Lab Accession: SCV002549910.1 First in ClinVar: Jul 28, 2022 Last updated: Jul 28, 2022
Pathogenic (Nov 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glaucoma 1, open angle, A Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835338.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Jul 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glaucoma 1, open angle, A (Autosomal dominant inheritance) Affected status: no Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086755.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 15069026‚ 30267046 Comment: 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 … (more) 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 (less)
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001371312.24 First in ClinVar: Jul 16, 2020 Last updated: Oct 20, 2024	Comment: MYOC: PP1:Strong, PVS1:Strong, PS3:Moderate, PS4:Moderate Number of individuals with the variant: 24
Pathogenic (Feb 01, 2003)	no assertion criteria provided Method: literature only	GLAUCOMA 1, OPEN ANGLE, A Affected status: not provided Allele origin: germline	OMIM Accession: SCV000028620.2 First in ClinVar: Apr 04, 2013 Last updated: Nov 09, 2018	Publications: PubMed (3) PubMed: 11535458‚ 12522550‚ 11292420 Stone, E. M. Personal (more...) Stone, E. M. Personal Communication. 1999. Iowa City, Iowa Stone, E. M. Personal (more...) Stone, E. M. Personal Communication. 1997. Iowa City, Iowa Comment on evidence: In 2 families with 1q-linked glaucoma (137750) included in an initial survey, Stone et al. (1997) found a nonsense mutation (glutamine to stop) in codon … (more) In 2 families with 1q-linked glaucoma (137750) included in an initial survey, Stone et al. (1997) found a nonsense mutation (glutamine to stop) in codon 368 of the TIGR gene (Q168X). The mutation would be expected to result in a 136-amino acid truncation of the gene product. Eight additional individuals harboring the gln368-to-ter mutation were identified by screening 4 different populations: glaucoma patients with a family history of the disease; unselected primary open angle glaucoma (POAG) probands seen in a single clinic; the general population; and unrelated volunteers over the age of 40 with normal intraocular pressures and no personal or family history of glaucoma. The gln368-to-ter mutation was found in 3 of 103 consecutive unrelated open angle glaucoma patients seen in a glaucoma clinic; it was found in 1 of 471 control subjects. Based on a cDNA sequence that contained a 7-codon error, this common mutation was originally referred to by Stone et al. (1997) as GLN361TER (Stone, 1999). Craig et al. (2001) studied the phenotype and age-related penetrance of primary open angle glaucoma in families with Q368X, the most common myocilin mutation in Australia. They found that the Q368X mutation was associated with primary open angle glaucoma with younger onset and higher peak intraocular pressure than nonmutation glaucoma cases. In addition, Q368X mutation glaucoma cases were more likely to have undergone glaucoma drainage surgery. They did not observe simple autosomal dominant inheritance patterns for primary open angle glaucoma in the 8 pedigrees studied. They concluded that other factors were involved in expression of the primary open angle glaucoma phenotype in Q368X pedigrees. To identify a possible founder, Baird et al. (2003) studied 15 'unrelated' POAG families from southeastern Australia who carried the Q368X mutation. In 1 large family, 9 affected and 10 unaffected individuals were identified with the mutation. Closely linked polymorphic microsatellite markers were used to establish a disease haplotype in this family. Additional genotyping of markers in the other 14 families revealed the presence of the same disease haplotype. These findings indicated that the mutation in all 15 families shared a common origin before the European settlement of Australia in the early 1800s. Baird et al. (2001) found that the use of the Taa1 restriction enzyme offered a relatively simple, rapid, and reproducible technique for detection of the Q368X mutation. (less)
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Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Myocilin Gene Gln368Ter Variant Penetrance and Association With Glaucoma in Population-Based and Registry-Based Studies.	Han X	JAMA ophthalmology	2019	PMID: 30267046
Glaucomatous MYOC mutations activate the IL-1/NF-κB inflammatory stress response and the glaucoma marker SELE in trabecular meshwork cells.	Itakura T	Molecular vision	2015	PMID: 26396484
Cellular processing of myocilin.	Qiu Y	PloS one	2014	PMID: 24732711
Compound heterozygote myocilin mutations in a pedigree with high prevalence of primary open-angle glaucoma.	Young TK	Molecular vision	2012	PMID: 23304066
Myocilin polymorphisms and primary open-angle glaucoma: a systematic review and meta-analysis.	Cheng JW	PloS one	2012	PMID: 23029558
Low prevalence of myocilin mutations in an African American population with primary open-angle glaucoma.	Liu W	Molecular vision	2012	PMID: 22933836
Variable clinical spectrum of the myocilin Gln368X mutation in a Dutch family with primary open angle glaucoma.	Hogewind BF	Current eye research	2010	PMID: 20021252
Heterozygous expression of myocilin glaucoma mutants increases secretion of the mutant forms and reduces extracellular processed myocilin.	Aroca-Aguilar JD	Molecular vision	2008	PMID: 19023451
Role of MYOC and OPTN sequence variations in Spanish patients with primary open-angle glaucoma.	Lopez-Martinez F	Molecular vision	2007	PMID: 17615537
Myocilin variants in Indian patients with open-angle glaucoma.	Bhattacharjee A	Archives of ophthalmology (Chicago, Ill. : 1960)	2007	PMID: 17562996
Reversal of mutant myocilin non-secretion and cell killing: implications for glaucoma.	Liu Y	Human molecular genetics	2004	PMID: 15069026
Myocilin analysis by DHPLC in French POAG patients: increased prevalence of Q368X mutation.	Melki R	Human mutation	2003	PMID: 12872267
Analysis of 15 primary open-angle glaucoma families from Australia identifies a founder effect for the Q368STOP mutation of myocilin.	Baird PN	Human genetics	2003	PMID: 12522550
Founder TIGR/myocilin mutations for glaucoma in the Québec population.	Faucher M	Human molecular genetics	2002	PMID: 12189160
Rapid mutation detection by the transgenomic wave analyser DHPLC identifies MYOC mutations in patients with ocular hypertension and/or open angle glaucoma.	Cobb CJ	The British journal of ophthalmology	2002	PMID: 11815346
MYOC mutation frequency in primary open-angle glaucoma patients from Western Switzerland.	Mataftsi A	Ophthalmic genetics	2001	PMID: 11803488
Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier.	Craig JE	Ophthalmology	2001	PMID: 11535458
The Taa1 restriction enzyme provides a simple means to identify the Q368STOP mutation of the myocilin gene in primary open angle glaucoma.	Baird PN	American journal of ophthalmology	2001	PMID: 11292420
Age-dependent prevalence of mutations at the GLC1A locus in primary open-angle glaucoma.	Shimizu S	American journal of ophthalmology	2000	PMID: 11004290
Myocilin Gln368stop mutation and advanced age as risk factors for late-onset primary open-angle glaucoma.	Angius A	Archives of ophthalmology (Chicago, Ill. : 1960)	2000	PMID: 10815160
A novel mutation in the GLC1A gene causes juvenile open-angle glaucoma in 4 families from the Italian region of Puglia.	Angius A	Archives of ophthalmology (Chicago, Ill. : 1960)	1998	PMID: 9639450
Identification of a gene that causes primary open angle glaucoma.	Stone EM	Science (New York, N.Y.)	1997	PMID: 9005853
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/399db6af-6807-459a-9953-39c259125cad	-	-	-	-
Stone, E. M. Personal Communication. 1997. Iowa City, Iowa	-	-	-	-
Stone, E. M. Personal Communication. 1999. Iowa City, Iowa	-	-	-	-
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Text-mined citations for rs74315329 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs74315329 ...