Submissions for variant NM_000261.2(MYOC):c.1021T>C (p.Ser341Pro)

dbSNP: rs1572210748

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Glaucoma Variant Curation Expert Panel	RCV003126018	SCV003803722	likely pathogenic	Glaucoma of childhood	2023-02-15	reviewed by expert panel	curation	The c.1021T>C variant in MYOC is a missense variant predicted to cause substitution of Serine by Proline at amino acid 341 (p.Ser341Pro). 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 = 0.821, which met the >=0.7 threshold for PP3, predicting a damaging effect on MYOC function. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. 12 segregations in 4 families, with juvenile or primary open angle glaucoma (JOAG or POAG), have been reported (PMIDs: 17867509, 24825108, 33214997, 25777973), which fulfilled PP1_Strong (>=7 meioses in >1 family). 8 probands with JOAG or POAG have been reported carrying this variant (PMIDs: 9510647, 24825108, 25777973, 33214997, 17867509, ClinVar: Invitae), which met PS4_Moderate (>=6 probands). In summary, this variant met the criteria to receive a score of 8 and to be classified as likely pathogenic (likely pathogenic classification range 6 to 9) 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, PP3, PS4_Moderate, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001965333	SCV002211821	pathogenic	not provided	2021-04-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with glaucoma (PMID: 9510647, 17867509, 25777973, 24825108). It has also been observed to segregate with disease in related individuals. This variant is also known as Pro334Ser. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 341 of the MYOC protein (p.Ser341Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline.