rs74315330

Variant names:

• chr1-171636331-G-A
• rs74315330
• NM_000261.2:c.1109C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-171636331-G-A
• chr1-171636331-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3 PM2_Supporting PS3_Moderate PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1109C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 370 (p.Pro370Leu). 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 = 0.89, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID:16466712) demonstrated that the Pro370Leu 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. 21 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9490287, 9772276), which fulfilled PP1_Strong (≥7 meioses in >1 family). 15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9345106, 9328473, 11774072, 28564705, 12447164, 22194650, 9792882, 23453510, 29540704, 30484747, 9490287, 9772276), which met PS4 (≥ 15 probands). There were many more probands and families published than presented here. In summary, this variant met the criteria to receive a score of 12 and to be classified as pathogenic (pathogenic classification ≥ 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PS4, PP1_Strong, PS3_Moderate, PP3, PM2_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA119171/MONDO:0020367/019

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 5.80
• Publications: 110 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: Pathogenic. The variant received 12 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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.
• PP3: 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.1109C>T	p.Pro370Leu	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.1109C>T	p.Pro370Leu	missense	Exon 3 of 3	ENSP00000037502.5	Q99972
	MYOC	ENST00000971579.1		c.1214C>T	p.Pro405Leu	missense	Exon 3 of 3	ENSP00000641638.1
	MYOC	ENST00000877923.1		c.1175C>T	p.Pro392Leu	missense	Exon 4 of 4	ENSP00000547982.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000396 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Glaucoma 1, open angle, A (4)
2	-	-	not provided (2)
1	-	-	Open-angle glaucoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.93		Loss of loop (P = 0.0986)
MVP		0.98
MPC		0.72
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.87
gMVP		0.91
Mutation Taster		=4/96	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: rs74315330; hg19: chr1-171605471; COSMIC: COSV50674332;