Variant: NM_000261.2(MYOC):c.1278C>T (p.Val426=)

CA421938719

806282 (ClinVar)

Gene: MYOC

Condition: primary open angle glaucoma

Inheritance Mode: Autosomal dominant inheritance

UUID: 87c501e6-d1e2-4548-9adb-bc595e3c4d4a

Approved on: 2023-05-03

Published on: 2023-05-03

HGVS expressions

NM_000261.2:c.1278C>T
NM_000261.2(MYOC):c.1278C>T (p.Val426=)
NC_000001.11:g.171636162G>A
CM000663.2:g.171636162G>A
NC_000001.10:g.171605302G>A
CM000663.1:g.171605302G>A
NC_000001.9:g.169871925G>A
NG_008859.1:g.21472C>T
ENST00000037502.11:c.1278C>T
ENST00000637303.1:c.235-2468G>A
ENST00000638471.1:c.*616C>T
ENST00000037502.10:c.1278C>T
ENST00000614688.1:c.*242C>T
NM_000261.1:c.1278C>T

Uncertain Significance

• Met criteria codes: PS4_Supporting BP7 BP4 PM2_Supporting

• Not Met criteria codes: PM5 PM4 BA1 PM6 BS3 BS1 PS2 PS1 PS3 PP1 PP3

Expert Panel

Glaucoma VCEP

Criteria Specification Information

Evidence submitted by expert panel

Glaucoma VCEP

The c.1278C>T variant in MYOC is a synonymous variant (p.Val426=). 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. This variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), with a CADD score (v1.6) = 0.173 which met the ≤ 10 threshold for BP4, and the GERP score = -10.1 (threshold < 0), indicating a lack of conservation at this site (BP7). This evidence suggests that the variant does not impact MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. Only 1 segregation had been reported for primary open angle glaucoma (personal communication from authors of PMID: 23922489), not meeting the ≥ 3 segregations required for PP1. 2 probands with primary open angle glaucoma have been reported carrying this variant (PMID: 22736945 and personal communication with authors of PMID: 23922489), which met PS4_Supporting (≥ 2 probands). In summary, this variant met the criteria to receive a score of 0 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): BP4, BP7, PS4_Supporting, PM2_Supporting

Met criteria codes

• PS4_Supporting: 2 probands with POAG have been reported carrying this variant (PMID: 22736945 and personal communication with authors of PMID: 23922489), which met PS4_Supporting (≥ 2 probands).
• BP7: This synonymous variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2) and had a GERP score = -10.1 (threshold <0), indicating a lack of conservation at this site.
• BP4: The CADD score (v1.6) = 0.173, which met the ≤ 10 threshold for BP4 and this variant was not predicted to affect splicing, as assessed with SpliceAI (≤ 0.2), suggesting that the variant does not impact MYOC function.
• PM2_Supporting: 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.

Not Met criteria codes

• PM5: This is not a missense variant.
• PM4: This variant does not cause a protein length change.
• BA1: This criterion was not met as PM2_Supporting has been met.
• PM6: This variant has not been identified de novo.
• BS3: No functional evidence has been found for this variant.
• BS1: This criterion was not met as PM2_Supporting has been met.
• PS2: This variant has not been identified de novo.
• PS1: An established pathogenic variant causing this same amino acid change has not been identified.
• PS3: No functional evidence has been found for this variant.
• PP1: Only 1 segregation had been reported for primary open angle glaucoma (personal communication from authors of PMID: 23922489), not meeting the ≥ 3 segregations required for PP1.
• PP3: This is not a missense variant.