rs74315339

Positions:

chr1-171652468-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS3_SupportingBS1

This summary comes from the ClinGen Evidence Repository: The c.144G>T variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 48 (p.Gln48His). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.007937, which met the ≥ 0.001 threshold set for BS1 (243 alleles out of 30,616, meeting the threshold of ≥ 5 of at least 2,000 observed alleles). The REVEL score = 0.257, 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. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Gln48His protein had similar solubility and secretion 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. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of - 6 and to be classified as likely benign (likely benign classification range - 2 to - 6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BS3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA119183/MONDO:0020367/019

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 11 hom. )

Consequence

MYOC
NM_000261.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel P:4B:4

Conservation

PhyloP100: -0.0120

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

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 link	c.144G>T	p.Gln48His	missense_variant	1/3	ENST00000037502.11	NP_000252.1	Q99972A0A0S2Z421

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOC	ENST00000037502.11 link	c.144G>T	p.Gln48His	missense_variant	1/3	1	NM_000261.2	ENSP00000037502.5		Q99972
MYOC	ENST00000638471.1 link	n.130+14G>T		intron_variant		5		ENSP00000491206.1		A0A1W2PP09

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00787

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000982

AC:

246

AN:

250544

Hom.:

AF XY:

0.00129

AC XY:

175

AN XY:

135524

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00794

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000501

AC:

733

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

518

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00800

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.000269

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00788

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000466

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00132

AC:

160

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:4Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glaucoma 1, open angle, A

Pathogenic:2Benign:1

Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000261.1:c.144G>T in the MYOC gene has an allele frequency of 0.008 in South Asian subpopulation in the gnomAD database.The MYOC c.144G>T (p.Gln48His) missense variant was identified in 4 of the 450 POAG patients (PMID: 22736945) and in two POAG patients from Chennai (PMID: 22194650). It was also observed in five of the eight glaucoma patients (PMID: 16288197). Chakrabarti S et al reported that the Gln48His mutation was detected in 9 different glaucoma patients (four POAG and five PCG) and all four POAG cases were heterozygous, among PCG cases, four were heterozygous and one exhibited homozygous genotype for the mutation(PMID: 15723004). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3, PS4, PP4 -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 17, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2005	- -

MYOC-related disorder

Pathogenic:1Benign:1

Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 24, 2022	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 30, 2017	Across a selection of the available literature, the MYOC c.144G>T (p.Gln48His) missense variant has been identified in a homozygous state in one individual with primary congenital glaucoma (PCG), and in a heterozygous state in 13 individuals with primary open angle glaucoma, eight with PCG, four with juvenile open angle glaucoma and five with microcoria and glaucoma (Mukhopadhyay et al. 2002; Sripriya et al. 2004; Chakrabarti et al. 2005; Kaur et al. 2005; Ramprasad et al. 2005; Kumar et al. 2007; Rose et al. 2011; Banerjee et al. 2012). The variant was absent from 1110 ethnically matched controls but is reported with a frequency of 0.02451 in the Sri Lankan Tamil in the UK population of the 1000 Genomes Project. This allele frequency is high but is consistent with the variant being one of the most commonly reported and well-described variants associated with glaucoma in the South Asian population (Sripriya et al. 2004; Ramprasad et al. 2005). The Gln48 residue is conserved. Based on the collective evidence, the p.Gln48His variant is classified as pathogenic for MYOC-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

GLAUCOMA 3, PRIMARY CONGENITAL, A, DIGENIC

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2005

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 02, 2023

- -

Glaucoma of childhood

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

Mar 05, 2022

The c.144G>T variant in MYOC is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 48 (p.Gln48His). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.007937, which met the >= 0.001 threshold set for BS1 (243 alleles out of 30,616, meeting the threshold of >= 5 of at least 2,000 observed alleles). The REVEL score = 0.257, 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. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Gln48His protein had similar solubility and secretion 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. As BS1 was met, PP1 did not apply and segregations were not counted. Although probands with juvenile or primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of - 6 and to be classified as likely benign (likely benign classification range - 2 to - 6) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS1, BS3_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.23

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.45

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.61

MetaRNN

Benign

0.022

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.25

REVEL

Benign

0.26

Sift

Benign

0.035

Sift4G

Uncertain

0.029

Polyphen

0.039

Vest4

0.25

MutPred

0.73

Gain of catalytic residue at Q48 (P = 0.0491);

MVP

0.74

MPC

0.17

ClinPred

0.91

GERP RS

0.19

Varity_R

0.052

gMVP

0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over