Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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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
Link to MONDO
UUID: 87c501e6-d1e2-4548-9adb-bc595e3c4d4a

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 4
PS4_Supporting PM2_Supporting BP4 BP7
Not Met criteria codes 11
PS2 PS1 PS3 BA1 PP1 PP3 PM6 PM5 PM4 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
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).
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.
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.
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.
Not Met criteria codes
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.
BA1
This criterion was not met as PM2_Supporting has been met.
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.
PM6
This variant has not been identified de novo.
PM5
This is not a missense variant.
PM4
This variant does not cause a protein length change.
BS3
No functional evidence has been found for this variant.
BS1
This criterion was not met as PM2_Supporting has been met.
Approved on: 2023-05-03
Published on: 2023-05-03
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