Submissions for variant NM_000261.2(MYOC):c.1334C>T (p.Ala445Val)

gnomAD frequency: 0.00035  dbSNP: rs140967767

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Glaucoma Variant Curation Expert Panel	RCV001843364	SCV002102556	likely benign	Glaucoma 1, open angle, E	2022-03-05	reviewed by expert panel	curation	The c.1334C>T variant in MYOC is a missense variant predicted to cause substitution of Alanine by Valine at amino acid 445 (p.Ala445Val). The highest minor allele frequency of this variant was in the non-Finnish European population of gnomAD (v2.1.1) = 0.0003406 (44 alleles out of 129,196), which did not meet the PM2_Supporting allele frequency threshold (<= 0.0001) or the BS1 allele frequency threshold (>= 0.001). The REVEL score = 0.472, which was neither above nor below the thresholds for PP3 (>= 0.7) or BP4 (<= 0.15), predicting a damaging or benign impact on MYOC function. Previous studies (PMIDs: 16466712 and 35196929) demonstrated that the Ala445Val protein had similar solubility and secretion levels to wild type myocilin protein and met the OddsPath threshold for BS3_Moderate (< 0.23), indicating that this variant did not impact protein function. Although probands with primary open angle glaucoma have been reported carrying this variant, PM2_Supporting was not met, therefore PS4 did not apply. In summary, this variant met the criteria to receive a score of -2 and to be classified as likely benign (likely benign classification range -2 to -6) for primary open angle glaucoma based on the ACMG/AMP criteria met, as specified by the ClinGen Glaucoma VCEP (v1, 12 Oct 2021): BS3_Moderate.
Illumina Laboratory Services, Illumina	RCV000778198	SCV000914362	likely pathogenic	MYOC-Related Disorders	2018-09-19	criteria provided, single submitter	clinical testing	The MYOC c.1334C>T (p.Ala445Val) missense variant has been reported in five studies in which it is found in a heterozygous state in a total of six probands including three probands with primary open angle glaucoma, two probands with glaucoma, and one proband with ocular hypertension (Alward et al. 1998; Vincent et al. 2002; Faucher et al. 2002; Weisschuh et al. 2005; Lopez-Martinez et al. 2007). At least two of these probands had a family history of glaucoma (Faucher et al. 2002; Vincent et al. 2002). The p.Ala445Val variant was absent from 723 controls but is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Functionally, the p.Ala445Val protein exhibited a similar effect as wild type in thermal stability analyses, but demonstrated increased in vitro aggregation relative to the wild type protein, as evaluated through size exclusion chromatography (Burns et al. 2011). The authors indicate that the data regarding the mechanism for the variant's effect were inconclusive but were suggestive of a pathogenic effect. Based on the collective evidence, the p.Ala445Val variant is classified as likely pathogenic for MYOC-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
CeGaT Center for Human Genetics Tuebingen	RCV001815434	SCV002062847	likely benign	not provided	2021-12-01	criteria provided, single submitter	clinical testing