1-171636010-A-T

Variant names:

• chr1-171636010-A-T
• rs74315331
• NM_000261.2:c.1430T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3_Moderate PS4_Supporting PM2_Supporting PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1430T>A variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Asparagine at amino acid 477 (p.Ile477Asn). 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 = 0.534, which was neither above nor below the thresholds for PP3 (≥ 0.7) or BP4 (≤ 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID:16466712) demonstrated that the Ile477Asn 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. 34 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9754180, 9535666), which fulfilled PP1_Strong (≥7 meioses in >1 family). 2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9754180, 9535666), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 8 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Moderate, PS4_Supporting, PM2_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA129023/MONDO:0020367/019

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.28
• Publications: 36 publications found

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

Our verdict: Likely_pathogenic. The variant received 8 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000261.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOC	NM_000261.2	MANE Select	c.1430T>A	p.Ile477Asn	missense	Exon 3 of 3	NP_000252.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOC	ENST00000037502.11	TSL:1 MANE Select	c.1430T>A	p.Ile477Asn	missense	Exon 3 of 3	ENSP00000037502.5
	MYOC	ENST00000638471.1	TSL:5	n.*768T>A		non_coding_transcript_exon	Exon 4 of 4	ENSP00000491206.1
	MYOC	ENST00000638471.1	TSL:5	n.*768T>A		3_prime_UTR	Exon 4 of 4	ENSP00000491206.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Glaucoma 1, open angle, A Pathogenic:1

Sep 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Glaucoma of childhood Pathogenic:1

May 09, 2022

ClinGen Glaucoma Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1430T>A variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Asparagine at amino acid 477 (p.Ile477Asn). 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 = 0.534, which was neither above nor below the thresholds for PP3 (>= 0.7) or BP4 (<= 0.15), predicting a damaging or benign impact on MYOC function. A previous study (PMID: 16466712) demonstrated that the Ile477Asn 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. 34 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9754180, 9535666), which fulfilled PP1_Strong (>=7 meioses in >1 family). 2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9754180, 9535666), which met PS4_Supporting (>= 2 probands). In summary, this variant met the criteria to receive a score of 8 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Moderate, PS4_Supporting, PM2_Supporting

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.3
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.57
MutPred		0.96		Gain of disorder (P = 0.0058)
MVP		0.96
MPC		0.94
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.96
gMVP		0.97
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs74315331; hg19: chr1-171605150;