rs74315335

chr1-171636430-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000261.2(MYOC):c.1010A>G(p.Gln337Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q337E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 6.21

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a disulfide_bond (size 188) in uniprot entity MYOC_HUMAN there are 57 pathogenic changes around while only 11 benign (84%) in NM_000261.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOC	NM_000261.2	c.1010A>G	p.Gln337Arg	missense_variant	3/3	ENST00000037502.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOC	ENST00000037502.11	c.1010A>G	p.Gln337Arg	missense_variant	3/3	1	NM_000261.2	P1
MYOCOS	ENST00000637303.1	c.235-2200T>C		intron_variant		5		A2
MYOC	ENST00000638471.1	c.*348A>G		3_prime_UTR_variant, NMD_transcript_variant	4/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glaucoma 1, open angle, A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1997

- -

Glaucoma of childhood Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

Aug 07, 2023

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	T
BayesDel_noAF	Pathogenic	0.34
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.74
Sift	Benign	0.076	T
Sift4G	Uncertain	0.038	D
Polyphen		0.47	P
Vest4		0.55
MutPred		0.91		Gain of MoRF binding (P = 0.0446);
MVP		0.96
MPC		0.51
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.78
gMVP		0.90

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

Other links and lift over

dbSNP: rs74315335; hg19: chr1-171605570;