1-171636010-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2_Supporting PS3_Supporting PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1430T>G variant in MYOC is a missense variant predicted to cause substitution of Isoleucine by Serine at amino acid 477 (p.Ile477Ser). 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 = 0.646, 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 Ile477Ser protein had increased insolubility levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Supporting (> 2.1), indicating that this variant did impact protein function. 20 segregations in 1 family, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9328473), 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:9328473), 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, PS3_Supporting, PM2_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA119174/MONDO:0020367/019

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PS3: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOC	NM_000261.2	MANE Select	c.1430T>G	p.Ile477Ser	missense	Exon 3 of 3	NP_000252.1	Q99972

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOC	ENST00000037502.11	TSL:1 MANE Select	c.1430T>G	p.Ile477Ser	missense	Exon 3 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.1535T>G	p.Ile512Ser	missense	Exon 3 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.1496T>G	p.Ile499Ser	missense	Exon 4 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Glaucoma 1, open angle, A (1)
-	1	-	Glaucoma of childhood (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.3
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.96	D
Vest4		0.55
MutPred		0.96		Gain of disorder (P = 6e-04)
MVP		0.96
MPC		0.77
ClinPred		0.94	D
GERP RS		4.9
Varity_R		0.94
gMVP		0.97
Mutation Taster		=11/89	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;