1-171636449-A-T

Position:

• chr1-171636449-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000261.2(MYOC):​c.991T>A​(p.Ser331Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign 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. S331L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOC NM_000261.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: -0.525

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000261.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOC	NM_000261.2	c.991T>A	p.Ser331Thr	missense_variant	3/3	ENST00000037502.11	NP_000252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOC	ENST00000037502.11	c.991T>A	p.Ser331Thr	missense_variant	3/3	1	NM_000261.2	ENSP00000037502.5
MYOCOS	ENST00000637303.1	c.235-2181A>T		intron_variant		5		ENSP00000490048.1
MYOC	ENST00000638471.1	n.*329T>A		non_coding_transcript_exon_variant	4/4	5		ENSP00000491206.1
MYOC	ENST00000638471.1	n.*329T>A		3_prime_UTR_variant	4/4	5		ENSP00000491206.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Open-angle glaucoma Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Glaucoma Variant Curation Expert Panel

Feb 15, 2023

The c.991T>A variant in MYOC is a missense variant predicted to cause substitution of Serine by Threonine at amino acid 331 (p.Ser331Thr). 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 = 0.543, 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. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 proband with primary open angle glaucoma had been reported (PMID: 17417611), not meeting the >=2 probands threshold required to meet PS4_Supporting. In summary, this variant met the criteria to receive a score of 1 and to be classified as a variant of uncertain significance (uncertain significance classification range -1 to 5) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PM2_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	3.4
DANN	Benign	0.48
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.54
Sift	Benign	0.073	T
Sift4G	Benign	0.48	T
Polyphen		0.069	B
Vest4		0.38
MutPred		0.79		Loss of glycosylation at S331 (P = 0.1413);
MVP		0.49
MPC		0.17
ClinPred		0.13	T
GERP RS		-5.7
Varity_R		0.26
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137853276; hg19: chr1-171605589;