rs74315335

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3PM2_SupportingPS4_SupportingPP1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1010A>G variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Arginine at amino acid 337 (p.Gln337Arg). 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 = 0.743, which met the ≥ 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 6 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 34923728, 9361308), which fulfilled PP1_Moderate (≥5 meioses). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 34923728, 32300215, 9361308), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 5 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, PP3, PS4_Supporting, PM2_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA119177/MONDO:0020367/019

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYOC
NM_000261.2 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:1

Conservation

PhyloP100: 6.21

Publications

14 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: Uncertain_significance. The variant received 5 ACMG points.

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.1010A>G	p.Gln337Arg	missense_variant	Exon 3 of 3	ENST00000037502.11	NP_000252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MYOC	ENST00000037502.11 link	c.1010A>G	p.Gln337Arg	missense_variant	Exon 3 of 3	1	NM_000261.2	ENSP00000037502.5
MYOC	ENST00000638471.1 link	n.*348A>G		non_coding_transcript_exon_variant	Exon 4 of 4	5		ENSP00000491206.1
MYOC	ENST00000638471.1 link	n.*348A>G		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000491206.1
MYOCOS	ENST00000637303.1 link	c.235-2200T>C		intron_variant	Intron 3 of 3	5		ENSP00000490048.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727246

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glaucoma 1, open angle, A

Pathogenic:1

Sep 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Glaucoma of childhood

Uncertain:1

Aug 07, 2023

ClinGen Glaucoma Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The c.1010A>G variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Arginine at amino acid 337 (p.Gln337Arg). 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 = 0.743, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 6 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 34923728, 9361308), which fulfilled PP1_Moderate (>=5 meioses). 4 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 34923728, 32300215, 9361308), which met PS4_Supporting (>= 2 probands). In summary, this variant met the criteria to receive a score of 5 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, PP3, PS4_Supporting, PM2_Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.62

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.94

MetaSVM

Benign

-0.55

MutationAssessor

Pathogenic

2.9

PhyloP100

6.2

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.5

REVEL

Pathogenic

0.74

Sift

Benign

0.076

Sift4G

Uncertain

0.038

Polyphen

0.47

Vest4

0.55

MutPred

0.91

Gain of MoRF binding (P = 0.0446);

MVP

0.96

MPC

0.51

ClinPred

0.97

GERP RS

5.8

Varity_R

0.78

gMVP

0.90

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over