ClinVar Genomic variation as it relates to human health

The c.1109C>T variant in MYOC is a missense variant predicted to cause substitution of Proline by Leucine at amino acid 370 (p.Pro370Leu). 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 = 0.89, which met the >= 0.7 threshold for PP3, predicting a damaging effect on MYOC function. A previous study (PMID: 16466712) demonstrated that the Pro370Leu protein had 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. 21 segregations in 2 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 9490287, 9772276), which fulfilled PP1_Strong (>=7 meioses in >1 family). 15 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9345106, 9328473, 11774072, 28564705, 12447164, 22194650, 9792882, 23453510, 29540704, 30484747, 9490287, 9772276), which met PS4 (>= 15 probands). There were many more probands and families published than presented here. In summary, this variant met the criteria to receive a score of 12 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): PS4, PP1_Strong, PS3_Moderate, PP3, PM2_Supporting

The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19023451). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.89). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 9328473). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 9345106). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

The missense c.1109C>T (p.Pro370Leu) variant in the MYOC gene has been observed in individual(s) with glaucoma (Svidnicki, Paulo Vinicius et al., 2018). It has also been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects MYOC function (Gobeil, Stéphane et al.,2006).The variant is absent in gnomAD Exomes. It is submitted to ClinVar as Pathogenic (reviwed by expert panel). The amino acid Proline at position 370 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Pro370Leu in MYOC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

The P370L missense variant in the MYOC gene has been reported previously in association with juvenile-onset primary open angle glaucoma (JOAG) (Adam et al., 1997; Li et al., 2014). The P370L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. P370L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the olfactomedin-like domain that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, in vitro functional studies demonstrated that co-expression of the P370L variant reduced the extracellular levels of normal myocilin protein over 10-fold (Aroca-Aguilar et al., 2008). Missense variants in nearby residues (G367R, F369L, Y371D, G374V) have been reported in the Human Gene Mutation Database in association with open angle glaucoma (Stenson et al., 2014), supporting the functional importance of this region of the protein.

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 370 of the MYOC protein (p.Pro370Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glaucoma (PMID: 18728751, 30484747). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7948). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYOC protein function. Experimental studies have shown that this missense change affects MYOC function (PMID: 16466712). For these reasons, this variant has been classified as Pathogenic.