1-171636000-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3PS3_ModeratePM2_SupportingPS4_ModeratePP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1440C>A variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 480 (p.Asn480Lys). 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 = 0.784, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Asn480Lys protein had increased insolubility and 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. Over 90 segregations in 8 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 12107514, 24883016, 9556305), which fulfilled PP1_Strong (≥ 7 meioses in > 1 family). 13 probands with JOAG or POAG have been reported carrying this variant (PMIDs: pers. communication E Souzeau, 22194650, 12872267, 12107514, 24883016, 9556305), which met PS4_Moderate (≥ 6 probands). In summary, this variant met the criteria to receive a score of 10 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): PP1_Strong, PS3_Moderate, PS4_Moderate, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA119175/MONDO:0020367/019

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MYOC
NM_000261.2 missense

Scores

6

10

3

Clinical Significance

Pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 2.53

Publications

26 publications found

Variant links:

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]

MYOC links:

MYOCOS (HGNC:53429): (myocilin opposite strand)

MYOCOS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOC	NM_000261.2 link	c.1440C>A	p.Asn480Lys	missense_variant	Exon 3 of 3	ENST00000037502.11	NP_000252.1	Q99972A0A0S2Z421

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOC	ENST00000037502.11 link	c.1440C>A	p.Asn480Lys	missense_variant	Exon 3 of 3	1	NM_000261.2	ENSP00000037502.5		Q99972
MYOC	ENST00000638471.1 link	n.*778C>A		non_coding_transcript_exon_variant	Exon 4 of 4	5		ENSP00000491206.1		A0A1W2PP09
MYOC	ENST00000638471.1 link	n.*778C>A		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000491206.1		A0A1W2PP09
MYOCOS	ENST00000637303.1 link	c.235-2630G>T		intron_variant	Intron 3 of 3	5		ENSP00000490048.1		A0A1B0GUC4

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD4 exome

AF:

0.00000137

AC:

2

AN:

1461882

Hom.:

0

Cov.:

31

AF XY:

0.00000275

AC XY:

2

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33480

American (AMR)

AF:

0.00

AC:

0

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

1

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

1

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

2

4

6

8

10

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

32

Alfa

AF:

0.00

Hom.:

0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glaucoma 1, open angle, A

Pathogenic:1

Apr 13, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

May 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 480 of the MYOC protein (p.Asn480Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with primary open angle glaucoma (PMID: 9328473, 22194650, 24883016). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7951). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYOC function (PMID: 16466712). For these reasons, this variant has been classified as Pathogenic. -

Glaucoma of childhood

Pathogenic:1

May 09, 2022

ClinGen Glaucoma Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.1440C>A variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 480 (p.Asn480Lys). 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 = 0.784, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Asn480Lys protein had increased insolubility and 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. Over 90 segregations in 8 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 12107514, 24883016, 9556305), which fulfilled PP1_Strong (>= 7 meioses in > 1 family). 13 probands with JOAG or POAG have been reported carrying this variant (PMIDs: pers. communication E Souzeau, 22194650, 12872267, 12107514, 24883016, 9556305), which met PS4_Moderate (>= 6 probands). In summary, this variant met the criteria to receive a score of 10 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): PP1_Strong, PS3_Moderate, PS4_Moderate, PP3, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.15

D

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

23

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.55

D

LIST_S2

Uncertain

0.89

D

M_CAP

Uncertain

0.18

D

MetaRNN

Pathogenic

0.99

D

MetaSVM

Uncertain

0.74

D

MutationAssessor

Pathogenic

4.0

H

PhyloP100

2.5

PrimateAI

Uncertain

0.53

T

PROVEAN

Pathogenic

-5.5

D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

D

Sift4G

Uncertain

0.0050

D

Polyphen

1.0

D

Vest4

0.87

MutPred

0.98

Gain of methylation at N480 (P = 0.0071);

MVP

0.98

MPC

0.77

ClinPred

1.0

D

GERP RS

0.23

Varity_R

0.98

gMVP

0.96

Mutation Taster

=1/99

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

Publications

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Other links and lift over

dbSNP: rs74315332; hg19: chr1-171605140; API