NM_000261.2(MYOC):c.1109C>T (p.Pro370Leu) AND Glaucoma 1, open angle, A

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: May 20, 2023
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:: RCV000008411.7

Allele description [Variation Report for NM_000261.2(MYOC):c.1109C>T (p.Pro370Leu)]

NM_000261.2(MYOC):c.1109C>T (p.Pro370Leu)

Gene:

MYOC:myocilin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q24.3

Genomic location:

Preferred name:

NM_000261.2(MYOC):c.1109C>T (p.Pro370Leu)

Other names:

NM_000261.2(MYOC):c.1109C>T

HGVS:

NC_000001.11:g.171636331G>A
NG_008859.1:g.21303C>T
NM_000261.2:c.1109C>TMANE SELECT
NP_000252.1:p.Pro370Leu
NC_000001.10:g.171605471G>A
NC_000001.10:g.171605471G>A
NM_000261.1:c.1109C>T
Q99972:p.Pro370Leu

Protein change:

P370L; PRO370LEU

Links:

UniProtKB: Q99972#VAR_005472; OMIM: 601652.0004; dbSNP: rs74315330

NCBI 1000 Genomes Browser:

rs74315330

Molecular consequence:

NM_000261.2:c.1109C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Glaucoma 1, open angle, A (GLC1A)
Synonyms:: Primary open angle glaucoma juvenile onset 1; Glaucoma hereditary, juvenile; Glaucoma, Dominant (Juvenile Onset)
Identifiers:: MONDO: MONDO:0007664; MedGen: C1842028; Orphanet: 98977; OMIM: 137750

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000028619	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 1997)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 9328473, 9345106
SCV002521214	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9328473, 9345106, 19023451, 25741868
SCV002556425	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 9, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005329397	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedin-homology domain of TIGR in familial open-angle glaucoma.

Adam MF, Belmouden A, Binisti P, Brézin AP, Valtot F, Béchetoille A, Dascotte JC, Copin B, Gomez L, Chaventré A, Bach JF, Garchon HJ.

Hum Mol Genet. 1997 Nov;6(12):2091-7.

PubMed [citation]

PMID:: 9328473

Mutations in the TIGR gene in familial primary open-angle glaucoma in Japan.

Suzuki Y, Shirato S, Taniguchi F, Ohara K, Nishimaki K, Ohta S.

Am J Hum Genet. 1997 Nov;61(5):1202-4. No abstract available.

PubMed [citation]

PMID:: 9345106
PMCID:: PMC1716051

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000028619.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a French family with 4 members and a second French family with 10 members affected with primary open angle glaucoma (137750), Adam et al. (1997) found a C-to-T transition at nucleotide 1109 of the MYOC gene, causing a pro370-to-leu (P370L) amino acid substitution.

In Japan, Suzuki et al. (1997) performed mutation analysis of the MYOC gene in 52 patients with primary open angle glaucoma and with a family history (50 pedigrees). Two patients in 1 family, a father and daughter, carried a heterozygous C-to-T transition at the second nucleotide in the codon corresponding to the 370 amino acid residue of the TIGR protein, resulting in a P370L amino acid substitution. The father was diagnosed with POAG at age 26 years, the daughter at age 16 years.

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

From 3billion, SCV002521214.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19023451). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.89). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 9328473). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 9345106). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Genetics and Molecular Pathology, SA Pathology, SCV002556425.2

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

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV005329397.1

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

Description

The missense c.1109C>T (p.Pro370Leu) variant in the MYOC gene has been observed in individual(s) with glaucoma (Svidnicki, Paulo Vinicius et al., 2018). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects MYOC function (Gobeil, Stéphane et al.,2006).The variant is absent in gnomAD Exomes. It is submitted to ClinVar as Pathogenic (reviwed by expert panel). The amino acid Proline at position 370 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Pro370Leu in MYOC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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