chr1-171636331-G-A

Position:

• chr1-171636331-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2_Supporting PS3_Moderate PS4 PP1_Strong PP3

This summary comes from the ClinGen Evidence Repository: The c.1109C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 370 (p.Pro370Leu). This variant was not found in any population of gnomAD (v2.1.1), meeting the ≤ 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.89, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID:16466712) demonstrated that the Pro370Leu 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. 21 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9490287, 9772276), which fulfilled PP1_Strong (≥7 meioses in >1 family). 15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9345106, 9328473, 11774072, 28564705, 12447164, 22194650, 9792882, 23453510, 29540704, 30484747, 9490287, 9772276), which met PS4 (≥ 15 probands). There were many more probands and families published than presented here. 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, PS3_Moderate, PP3, PM2_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA119171/MONDO:0020367/019

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 5.80

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.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOC	NM_000261.2	c.1109C>T	p.Pro370Leu	missense_variant	3/3	ENST00000037502.11	NP_000252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOC	ENST00000037502.11	c.1109C>T	p.Pro370Leu	missense_variant	3/3	1	NM_000261.2	ENSP00000037502.5
MYOCOS	ENST00000637303.1	c.235-2299G>A		intron_variant		5		ENSP00000490048.1
MYOC	ENST00000638471.1	n.*447C>T		non_coding_transcript_exon_variant	4/4	5		ENSP00000491206.1
MYOC	ENST00000638471.1	n.*447C>T		3_prime_UTR_variant	4/4	5		ENSP00000491206.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Glaucoma 1, open angle, A Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 09, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2016	The P370L missense variant in the MYOC gene has been reported previously in association with juvenile-onset primary open angle glaucoma (JOAG) (Adam et al., 1997; Li et al., 2014). The P370L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. P370L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the olfactomedin-like domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, in vitro functional studies demonstrated that co-expression of the P370L variant reduced the extracellular levels of normal myocilin protein over 10-fold (Aroca-Aguilar et al., 2008). Missense variants in nearby residues (G367R, F369L, Y371D, G374V) have been reported in the Human Gene Mutation Database in association with open angle glaucoma (Stenson et al., 2014), supporting the functional importance of this region of the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 26, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 370 of the MYOC protein (p.Pro370Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glaucoma (PMID: 18728751, 30484747). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7948). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYOC protein function. Experimental studies have shown that this missense change affects MYOC function (PMID: 16466712). For these reasons, this variant has been classified as Pathogenic. -

Glaucoma of childhood Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

Mar 05, 2022

The c.1109C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 370 (p.Pro370Leu). This variant was not found in any population of gnomAD (v2.1.1), meeting the <= 0.0001 threshold set for PM2_Supporting in a population of at least 10,000 alleles. The REVEL score = 0.89, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Pro370Leu 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. 21 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9490287, 9772276), which fulfilled PP1_Strong (>=7 meioses in >1 family). 15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9345106, 9328473, 11774072, 28564705, 12447164, 22194650, 9792882, 23453510, 29540704, 30484747, 9490287, 9772276), which met PS4 (>= 15 probands). There were many more probands and families published than presented here. 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, PS3_Moderate, PP3, PM2_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.93		Loss of loop (P = 0.0986);
MVP		0.98
MPC		0.72
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.87
gMVP		0.91

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: rs74315330; hg19: chr1-171605471; COSMIC: COSV50674332;