rs74315341

chr1-171636686-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000261.2(MYOC):c.754G>A(p.Gly252Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 3.19

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 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000261.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 1-171636686-C-T is Pathogenic according to our data. Variant chr1-171636686-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7960.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.754G>A	p.Gly252Arg	missense_variant	3/3	ENST00000037502.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOC	ENST00000037502.11	c.754G>A	p.Gly252Arg	missense_variant	3/3	1	NM_000261.2	P1
MYOCOS	ENST00000637303.1	c.235-1944C>T		intron_variant		5		A2
MYOC	ENST00000638471.1	c.*92G>A		3_prime_UTR_variant, NMD_transcript_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450530 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722028

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

Glaucoma of childhood Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

Feb 20, 2022

The c.754G>A variant in MYOC is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 252 (p.Gly252Arg). 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 = 0.798, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Gly252Arg 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. 17 segregations in 3 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17210859, 10873982, 15326130), which fulfilled PP1_Strong (>= 7 meioses in > 1 family). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 17210859, 10873982, 9772276, 15326130), which met PS4_Supporting (>= 2 probands). In summary, this variant met the criteria to receive a score of 9 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, PP3, PM2_Supporting, PS4_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.84		Gain of solvent accessibility (P = 0.0306);
MVP		0.99
MPC		0.78
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.90
gMVP		0.87

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: rs74315341; hg19: chr1-171605826;