Variant classification summary

NM_000261.2:c.719A>G

MYOC · NP_000252.1:p.(Glu240Gly) · NM_000261.2

GRCh37: chr1:171607748 T>C · GRCh38: chr1:171638608 T>C

Gene: MYOC Transcript: NM_000261.2

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MYOC

Transcript

NM_000261.2

Protein

NP_000252.1:p.(Glu240Gly)

gnomAD AF

3.717135872467546e-06 (v4.1)

ClinVar

Uncertain Significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000261.2:c.719A>G (p.Glu240Gly) in MYOC is a rare missense variant absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF = 3.72e-06, 6/1,614,146 alleles), meeting PM2 at supporting strength per the ClinGen Glaucoma VCEP v2.1.

2

The REVEL score of 0.205 falls within the VCEP BP4 supporting range (0.184-0.290), and SpliceAI predicts no splice impact (max delta = 0.01), meeting BP4 at supporting strength.

3

This variant has been reported in ClinVar as Uncertain Significance by the ClinGen Glaucoma Variant Curation Expert Panel (ClinVar ID 2442275, reviewed by expert panel).

4

No functional studies, de novo reports, proband counts, or segregation data were identified for this variant in the available literature. PS1, PS2, PS3, PS4, PP1, and BS3 remain not assessed due to absence of data.

5

Under the Glaucoma VCEP v2.1 point-based scoring system, the variant accumulates +1 point (PM2_supporting) and -1 point (BP4_supporting), yielding a total of 0 points, which falls within the Uncertain Significance range (-1 to 5 points).

Final determination: ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYOC Version 2.1 v2.1 point-based framework yields a total score of 0, which maps to VUS under the specified Tavtigian-style ranges.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is not applicable per the ClinGen Glaucoma VCEP v2.1. MYOC disease mechanism is gain-of-function, not loss-of-function, and PVS1 is reserved for truncating variants via PM4 in this framework. NM_000261.2:c.719A>G is a missense variant (p.Glu240Gly).	cspec
PS1	Not met	No previously established pathogenic or likely pathogenic variant with the same amino acid change (p.Glu240Gly) has been reported. This variant itself is classified as Uncertain Significance by the ClinGen Glaucoma VCEP (ClinVar ID 2442275).	clinvar cspec
PS2	Not assessed	No de novo reports were identified for NM_000261.2:c.719A>G (p.Glu240Gly) in the literature. PS2 requires confirmed or assumed de novo occurrence in JOAG or POAG per the Glaucoma VCEP v2.1.
PS3	Not assessed	No functional assay data (solubility, secretion, or aggregation assays with OddsPath calculations) were identified for NM_000261.2:c.719A>G (p.Glu240Gly) in the literature. PS3 per the Glaucoma VCEP v2.1 requires well-established functional studies with OddsPath thresholds.
PS4	Not assessed	No proband counts from independent studies were identified for NM_000261.2:c.719A>G (p.Glu240Gly). PS4 per the Glaucoma VCEP v2.1 requires at least 2 probands with JOAG or POAG from multiple independent studies for supporting-level evidence.	clinvar
PS5	N/A	PS5 is not defined in the ClinGen Glaucoma VCEP v2.1 and is of the same class as PP5/BP6 (reputable source reports), which the VCEP explicitly marks as Not Applicable per ClinGen SVI VCEP Review Committee recommendations.	cspec
PM1	N/A	PM1 is not applicable per the ClinGen Glaucoma VCEP v2.1. MYOC has no mutational hotspot and benign variants are present throughout the well-characterized olfactomedin domain in exon 3.	cspec
PM2	Met	NM_000261.2:c.719A>G is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (AF = 3.72e-06, 6/1,614,146 alleles, 0 homozygotes; grpmax FAF = 1.83e-06). This meets the Glaucoma VCEP PM2 threshold of allele frequency ≤ 0.0001 (0.01%) at supporting strength.	gnomad_v2 gnomad_v4 cspec
PM5	Not met	PM5 is not met for NM_000261.2:c.719A>G (p.Glu240Gly). The Glaucoma VCEP v2.1 requires both (a) a previously established pathogenic or likely pathogenic variant at the same residue (Glu240) assessed independently of PM5, and (b) the variant must meet PP3. No established P/LP variants exist at position 240. Additionally, PP3 is not met (REVEL = 0.205, below the supporting threshold of 0.644).	pm5_candidates cspec revel
PM6	N/A	PM6 is not applicable per the ClinGen Glaucoma VCEP v2.1. The VCEP directs users to refer to PS2 for de novo evidence instead.	cspec
PP1	Not assessed	No co-segregation data were identified for NM_000261.2:c.719A>G (p.Glu240Gly). PP1 per the Glaucoma VCEP v2.1 requires at least 3 informative meioses for supporting-level evidence.
PP2	N/A	PP2 is not applicable per the ClinGen Glaucoma VCEP v2.1. Although pathogenic missense variants are common in MYOC, the gene has a significant amount of benign missense variation (gnomAD missense constraint z = 0.52), supporting tolerance to variation.	cspec
PP3	Not met	PP3 is not met for NM_000261.2:c.719A>G (p.Glu240Gly). The REVEL score is 0.205, which falls below the Glaucoma VCEP PP3 supporting threshold of 0.644. BayesDel score is -0.343, which is also in the benign range.	revel bayesdel cspec
PP4	N/A	PP4 is not applicable per the ClinGen Glaucoma VCEP v2.1. The phenotype associated with MYOC variants is not highly specific and there is genetic heterogeneity in glaucoma.	cspec
PP5	N/A	PP5 is not applicable per the ClinGen Glaucoma VCEP v2.1. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	BA1 is not met. The highest population allele frequency for NM_000261.2:c.719A>G is 5.08e-06 in the European (non-Finnish) population, far below the Glaucoma VCEP BA1 threshold of ≥0.01 (1%).	gnomad_v4 cspec
BS1	Not met	BS1 is not met. The highest population allele frequency for NM_000261.2:c.719A>G is 5.08e-06, far below the Glaucoma VCEP BS1 threshold of ≥0.001 (0.1%). The variant is absent from gnomAD v2.1 and present only at extremely low frequency in gnomAD v4.1.	gnomad_v2 gnomad_v4 cspec
BS2	N/A	BS2 is not applicable per the ClinGen Glaucoma VCEP v2.1. MYOC variants have incomplete penetrance and late age of onset, making the observation of a variant in a healthy individual uninformative.	cspec
BS3	Not assessed	No functional assay data demonstrating normal solubility or secretion were identified for NM_000261.2:c.719A>G (p.Glu240Gly). BS3 per the Glaucoma VCEP v2.1 requires functional studies with OddsPath <0.23 (moderate) or <0.48 (supporting).
BS4	N/A	BS4 is not applicable per the ClinGen Glaucoma VCEP v2.1. Phenocopies, reduced age-related penetrance, and the possibility of multiple pathogenic variants make non-segregation difficult to assess in MYOC-associated glaucoma.	cspec
BP1	N/A	BP1 is not applicable per the ClinGen Glaucoma VCEP v2.1. Both truncating and missense MYOC variants are causative; the gene is not one for which primarily truncating variants cause disease.	cspec
BP2	N/A	BP2 is not applicable per the ClinGen Glaucoma VCEP v2.1. Variants occurring in cis or trans are not reliably interpretable given variable phenotype and potential synergistic effects.	cspec
BP4	Met	BP4 is met at supporting strength per the Glaucoma VCEP v2.1. The REVEL score for NM_000261.2:c.719A>G (p.Glu240Gly) is 0.205, falling within the supporting benign range of 0.184-0.290 for missense variants. Additionally, SpliceAI predicts no splice impact (max delta = 0.01, ≤0.1).	revel spliceai cspec
BP5	N/A	BP5 is not applicable per the ClinGen Glaucoma VCEP v2.1. Multiple molecular diagnoses are possible in glaucoma and variants in different genes could have additive effects.	cspec
BP6	N/A	BP6 is not applicable per the ClinGen Glaucoma VCEP v2.1. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 is not applicable. NM_000261.2:c.719A>G is a missense variant (p.Glu240Gly), not an intronic, noncoding, or synonymous variant. The Glaucoma VCEP v2.1 restricts BP7 to intronic/noncoding and synonymous exonic variants that also meet BP4.	cspec

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