NM_000261.2(MYOC):c.1102C>T (p.Gln368Ter) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Aug 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001200372.28

Allele description [Variation Report for NM_000261.2(MYOC):c.1102C>T (p.Gln368Ter)]

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

Gene:

MYOC:myocilin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q24.3

Genomic location:

Preferred name:

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

Other names:

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

HGVS:

NC_000001.11:g.171636338G>A
NG_008859.1:g.21296C>T
NM_000261.2:c.1102C>TMANE SELECT
NP_000252.1:p.Gln368Ter
NC_000001.10:g.171605478G>A
NC_000001.10:g.171605478G>A
NM_000261.1:c.1102C>T

Protein change:

Q368*; GLN368TER

Links:

OMIM: 601652.0003; dbSNP: rs74315329

NCBI 1000 Genomes Browser:

rs74315329

Molecular consequence:

NM_000261.2:c.1102C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001371312	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Aug 1, 2024)	germline	clinical testing	Citation Link,
SCV002562489	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 11, 2023)	germline	clinical testing	Citation Link,
SCV003256865	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10815160, 11004290, 23029558, 19023451, 26396484, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001371312

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Aug 1, 2024)

germline

clinical testing

Citation Link,

SCV002562489

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Dec 11, 2023)

germline

clinical testing

Citation Link,

SCV003256865

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	24	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Myocilin Gln368stop mutation and advanced age as risk factors for late-onset primary open-angle glaucoma.

Angius A, Spinelli P, Ghilotti G, Casu G, Sole G, Loi A, Totaro A, Zelante L, Gasparini P, Orzalesi N, Pirastu M, Bonomi L.

Arch Ophthalmol. 2000 May;118(5):674-9.

PubMed [citation]

PMID:: 10815160

Age-dependent prevalence of mutations at the GLC1A locus in primary open-angle glaucoma.

Shimizu S, Lichter PR, Johnson AT, Zhou Z, Higashi M, Gottfredsdottir M, Othman M, Moroi SE, Rozsa FW, Schertzer RM, Clarke MS, Schwartz AL, Downs CA, Vollrath D, Richards JE.

Am J Ophthalmol. 2000 Aug;130(2):165-77.

PubMed [citation]

PMID:: 11004290

See all PubMed Citations (6)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001371312.24

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	24	not provided	not provided	clinical testing	not provided

Description

MYOC: PP1:Strong, PVS1:Strong, PS3:Moderate, PS4:Moderate

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		24	not provided	not provided	not provided

From GeneDx, SCV002562489.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003256865.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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