1-171635945-T-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000261.2(MYOC):c.1495A>T(p.Ile499Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I499S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: -0.827

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 20 ACMG points.

• PS1: Transcript NM_000261.2 (MYOC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a domain Olfactomedin-like (size 259) in uniprot entity MYOC_HUMAN there are 80 pathogenic changes around while only 16 benign (83%) in NM_000261.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 1-171635945-T-A is Pathogenic according to our data. Variant chr1-171635945-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1686792.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOC	NM_000261.2	c.1495A>T	p.Ile499Phe	missense_variant	3/3	ENST00000037502.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOC	ENST00000037502.11	c.1495A>T	p.Ile499Phe	missense_variant	3/3	1	NM_000261.2	P1
MYOCOS	ENST00000637303.1	c.235-2685T>A		intron_variant		5		A2
MYOC	ENST00000638471.1	c.*833A>T		3_prime_UTR_variant, NMD_transcript_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Glaucoma of childhood Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

May 09, 2022

The c.1495A>T variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Phenylalanine at amino acid 499 (p.Ile499Phe). 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 = 0.67, 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 Ile499Phe 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. 6 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 9328473), which fulfilled PP1_Moderate (5-6 meioses). 2 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 12872267, 9328473), which met PS4_Supporting (>= 2 probands). In summary, this variant met the criteria to receive a score of 6 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): PS3_Moderate, PP1_Moderate, PS4_Supporting, PM2_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	19
Dann	Uncertain	0.97
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	0.54	D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Polyphen		0.86	P
Vest4		0.85
MutPred		0.93		Gain of catalytic residue at I499 (P = 0.0632);
MVP		0.87
MPC		0.75
ClinPred		0.99	D
GERP RS		-6.6
Varity_R		0.78
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-171605085;