ClinVar Miner

Submissions for variant NM_000261.2(MYOC):c.1440C>A (p.Asn480Lys)

dbSNP: rs74315332
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Glaucoma Variant Curation Expert Panel RCV002247271 SCV002520341 pathogenic Glaucoma of childhood 2022-05-09 reviewed by expert panel curation The c.1440C>A variant in MYOC is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 480 (p.Asn480Lys). 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 = 0.784, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Asn480Lys protein had increased insolubility and reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. Over 90 segregations in 8 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 12107514, 24883016, 9556305), which fulfilled PP1_Strong (>= 7 meioses in > 1 family). 13 probands with JOAG or POAG have been reported carrying this variant (PMIDs: pers. communication E Souzeau, 22194650, 12872267, 12107514, 24883016, 9556305), which met PS4_Moderate (>= 6 probands). In summary, this variant met the criteria to receive a score of 10 and to be classified as pathogenic (pathogenic classification >= 10) for juvenile open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): PP1_Strong, PS3_Moderate, PS4_Moderate, PP3, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV005089209 SCV005834279 pathogenic not provided 2024-05-18 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 480 of the MYOC protein (p.Asn480Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with primary open angle glaucoma (PMID: 9328473, 22194650, 24883016). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7951). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MYOC function (PMID: 16466712). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000008414 SCV000028622 pathogenic Glaucoma 1, open angle, A 1998-04-13 no assertion criteria provided literature only

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