rs74315329

Positions:

• chr1-171636338-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP1_Strong PS4 PM4 PS3_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:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: MYOC NM_000261.2 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:12 B:1
• Conservation: PhyloP100: 3.44

Genes affected

MYOC (HGNC:7610): (myocilin) MYOC encodes the protein myocilin, which is believed to have a role in cytoskeletal function. MYOC is expressed in many occular tissues, including the trabecular meshwork, and was revealed to be the trabecular meshwork glucocorticoid-inducible response protein (TIGR). The trabecular meshwork is a specialized eye tissue essential in regulating intraocular pressure, and mutations in MYOC have been identified as the cause of hereditary juvenile-onset open-angle glaucoma. [provided by RefSeq, Jul 2008]

MYOCOS (HGNC:53429): (myocilin opposite strand)

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: 129 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00111 AC: 279 AN: 251404 Hom.: 0 AF XY: 0.00119 AC XY: 162 AN XY: 135874

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00119 AC: 1741 AN: 1461842 Hom.: 1 Cov.: 31 AF XY: 0.00118 AC XY: 859 AN XY: 727232

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00356

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000848 AC: 129 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.000807 AC XY: 60 AN XY: 74370

Gnomad4 AFR AF: 0.000386

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000718

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Glaucoma 1, open angle, A Pathogenic:6 Benign: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A
Vest4		0.87
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74315329; hg19: chr1-171605478; COSMIC: COSV50674786;