1-171635925-T-C

Position:

• chr1-171635925-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP1_Moderate PM2_Supporting PM4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1515A>G variant in MYOC is a single nucleotide change, predicted to substitute the terminating codon by Tryptophan and extending the protein by an additional 42 amino acids (p.Ter505TrpextTer42). This variant is predicted to involve < 10% of the protein within the conserved olfactomedin domain, meeting PM4_Supporting. 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. There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. 20 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID:34923728), which fulfilled PP1_Moderate (≥ 5 meioses in ≥ 1 family, but not the ≥ 7 meioses in > 1 family for the strong criterion). Only 1 proband with JOAG had been reported (PMID:34923728), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PM2_Supporting, PM4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343722726/MONDO:0020367/019

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC NM_000261.2 stop_lost
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 2.17

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM4: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.1515A>G	p.Ter505TrpextTer42	stop_lost	3/3	ENST00000037502.11	NP_000252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOC	ENST00000037502.11	c.1515A>G	p.Ter505TrpextTer42	stop_lost	3/3	1	NM_000261.2	ENSP00000037502	P1
MYOCOS	ENST00000637303.1	c.235-2705T>C		intron_variant		5		ENSP00000490048	A2
MYOC	ENST00000638471.1	c.*853A>G		3_prime_UTR_variant, NMD_transcript_variant	4/4	5		ENSP00000491206

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glaucoma of childhood Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

May 02, 2023

The c.1515A>G variant in MYOC is a single nucleotide change, predicted to substitute the terminating codon by Tryptophan and extending the protein by an additional 42 amino acids (p.Ter505TrpextTer42). This variant is predicted to involve < 10% of the protein within the conserved olfactomedin domain, meeting PM4_Supporting. 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. There was no computational or functional evidence predicting a damaging or benign impact of this variant on MYOC function. 20 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMID: 34923728), which fulfilled PP1_Moderate (>=5 meioses in >=1 family, but not the >=7 meioses in > 1 family for the strong criterion). Only 1 proband with JOAG had been reported (PMID: 34923728), not meeting the >=2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 4 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Moderate, PM2_Supporting, PM4_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	14
DANN	Benign	0.71
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.22	N
MutationTaster	Benign	1.0	N
Vest4		0.14
GERP RS		4.9

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: chr1-171605065;