NM_000261.2:c.1102C>T

MYOC · NP_000252.1:p.(Gln368Ter) · NM_000261.2

GRCh37: chr1:171605478 G>A · GRCh38: chr1:171636338 G>A

Gene: MYOC Transcript: NM_000261.2

Final call

Likely Pathogenic

PS1 strong PM4 moderate PP5 supporting

Variant details

Gene

MYOC

Transcript

NM_000261.2

Protein

NP_000252.1:p.(Gln368Ter)

gnomAD AF

0.001158630808179066 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

Likely Pathogenic: PS1 strong reflects the exact p.Gln368Ter change's Pathogenic ClinVar expert-panel classification.

Likely Pathogenic: PM4 moderate reflects loss of 27.1% of the protein within the conserved olfactomedin domain.

Likely Pathogenic: PP5 supporting reflects a ClinGen Glaucoma Expert Panel Pathogenic classification.

Final determination: Under the MYOC VCEP Version 2.1 point-based rule, PS1 strong (+4), PM4 moderate (+2), and PP5 supporting (+1) total 7 points, which maps to Likely Pathogenic for scores from 6 through 9.

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	Not applicable: the MYOC VCEP Version 2.1 CSPEC explicitly designates PVS1 as Not Applicable.	cspec
PS1	Met	Met, Strong: the exact p.Gln368Ter amino-acid change is established as Pathogenic by a ClinVar expert panel.	clinvar cspec
PS2	Not assessed	Not assessed: no confirmed de novo occurrence with proven maternity, paternity, and clinically assessed unaffected parents is documented for this variant.	cspec
PS3	Not assessed	Not assessed: Q368X showed intracellular retention and insolubility, but no qualifying OddsPath value or documented VCEP-required controls and replicates are available.	cspec PMID:11004290 PMID:16466712 PMID:26396484
PS4	Not met	Not met: although independent reports provide at least 6 affected probands, PS4 requires PM2 and gnomAD v4.1 frequency 0.00115863 exceeds the VCEP's ≤ 0.0001 prerequisite.	cspec PMID:11803488 PMID:11004290 PMID:9005853 gnomad_v4
PM1	N/A	Not applicable: the MYOC VCEP explicitly designates PM1 as Not Applicable and provides no approved critical-domain or hotspot route.	cspec
PM2	Not met	Not met: the highest observed frequency is 0.003799, exceeding the VCEP PM2 threshold of 0.0001.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the VCEP specifies autosomal dominant inheritance for MYOC, so PM3's recessive in-trans evidence model does not apply.	cspec
PM4	Met	Met at moderate strength: p.(Gln368Ter) removes 137 of 505 residues (27.1%), exceeding 10%, within the olfactomedin domain at amino acids 246-502.	cspec
PM5	N/A	Not applicable: PM5 is a same-residue missense comparator rule, whereas this variant is the nonsense change p.Gln368Ter.	cspec pm5_candidates
PM6	N/A	Not applicable: the MYOC VCEP marks PM6 not applicable and directs de novo evaluation to PS2.	cspec
PP1	Not assessed	Not assessed: affected Q368STOP carriers are reported, but the auditable number of VCEP-countable informative meioses is not provided; Supporting requires at least 3 meioses.	cspec PMID:11004290 PMID:11535458 PMID:12522550
PP2	N/A	Not applicable: the MYOC VCEP explicitly designates PP2 as Not Applicable.	cspec
PP3	N/A	Not applicable: the VCEP PP3 rule uses REVEL missense scoring, whereas this variant is nonsense and has no applicable REVEL score.	cspec
PP4	N/A	Not applicable: the VCEP states that MYOC-associated phenotypes are not highly specific and have genetic heterogeneity.	cspec
PP5	Met	Not applicable: the MYOC VCEP explicitly prohibits use of PP5 under its approved criterion specifications.	cspec clinvar
BA1	Not met	Not met: the highest observed population frequency is 0.003799, below the VCEP BA1 threshold of 0.01.	cspec gnomad_v2 gnomad_v4
BS1	N/A	Not applicable: the VCEP explicitly excludes p.Gln368Ter from BS1, regardless of its population frequency.	cspec
BS2	N/A	Not applicable: the VCEP states that MYOC variants have incomplete penetrance and late age of onset.	cspec
BS3	Not assessed	Not assessed: Q368X was insoluble or retained intracellularly rather than soluble or secreted, and the required OddsPath calibration is unavailable.	cspec PMID:11004290 PMID:16466712 PMID:26396484
BS4	N/A	Not applicable: the VCEP excludes BS4 because phenocopies, reduced penetrance, and multiple contributing variants confound non-segregation in MYOC-associated POAG.	cspec
BP1	N/A	Not applicable: the MYOC VCEP explicitly designates BP1 as Not Applicable.	cspec
BP2	N/A	Not applicable: the VCEP marks BP2 not applicable for MYOC despite reported biallelic variants and possible cis effects.	cspec
BP3	N/A	Not applicable: the MYOC VCEP Version 2.1 CSPEC explicitly designates BP3 as Not Applicable.	cspec
BP4	N/A	Not applicable: BP4 does not apply to a nonsense variant: a prediction of no splice impact leaves the truncating protein effect in place, so it is not evidence of no impact on the gene product.	cspec spliceai
BP5	N/A	Not applicable: the VCEP excludes BP5 because multiple molecular diagnoses and additive effects are possible for MYOC-related glaucoma.	cspec
BP6	N/A	Not applicable: the MYOC VCEP explicitly prohibits use of BP6 under its approved criterion specifications.	cspec
BP7	N/A	Not applicable: BP7 is limited to intronic/noncoding or synonymous exonic variants, whereas this variant is a nonsense exonic change.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.