1-171635957-C-T

Position:

• chr1-171635957-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_Supporting BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1483G>A variant in MYOC is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 495 (p.Val495Ile). 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 = 0.424, 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:10545602) demonstrated that the Val495Ile protein had similar solubility levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Only 1 proband with primary open angle glaucoma had been reported (PMID:9535666), not meeting the ≥ 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS3_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA343722912/MONDO:0007665/019

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 3.37

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 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.1483G>A	p.Val495Ile	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.1483G>A	p.Val495Ile	missense_variant	3/3	1	NM_000261.2	ENSP00000037502	P1
MYOCOS	ENST00000637303.1	c.235-2673C>T		intron_variant		5		ENSP00000490048	A2
MYOC	ENST00000638471.1	c.*821G>A		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 1, open angle, E Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

May 09, 2022

The c.1483G>A variant in MYOC is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 495 (p.Val495Ile). 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 = 0.424, 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: 10545602) demonstrated that the Val495Ile protein had similar solubility levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 9535666), not meeting the >= 2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of -1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS3_Moderate, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.72	N
REVEL	Uncertain	0.42
Sift	Benign	0.14	T
Sift4G	Benign	0.080	T
Polyphen		0.99	D
Vest4		0.21
MutPred		0.21		Gain of catalytic residue at V495 (P = 0.1019);
MVP		0.90
MPC		0.63
ClinPred		0.94	D
GERP RS		3.9
Varity_R		0.48
gMVP		0.66

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: chr1-171605097;