VCV000875033.5 - ClinVar

NM_000261.2(MYOC):c.1345G>A (p.Val449Ile)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Uncertain significance

for Open-angle glaucoma

Classification is based on the expert panel submission

Aug 2023 by ClinGen Glaucoma Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000261.2(MYOC):c.1345G>A (p.Val449Ile)

Variation ID: 875033 Accession: VCV000875033.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q24.3 1: 171636095 (GRCh38) [ NCBI UCSC ] 1: 171605235 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 31, 2020	Aug 13, 2023	Aug 7, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000261.2:c.1345G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000252.1:p.Val449Ile	missense
NC_000001.11:g.171636095C>T
NC_000001.10:g.171605235C>T
NG_008859.1:g.21539G>A

Protein change

V449I

Other names

NM_000261.2(MYOC):c.1345G>A
p.Val449Ile

Canonical SPDI

NC_000001.11:171636094:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00006

Exome Aggregation Consortium (ExAC) 0.00009

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

dbSNP: rs572512491 ClinGen: CA1244035 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MYOC		-	-	GRCh38 GRCh37	321	349

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Glaucoma	Uncertain significance (1)	criteria provided, single submitter	Apr 28, 2017	RCV001098516.4
Glaucoma 1, open angle, A	Uncertain significance (1)	criteria provided, single submitter	Apr 28, 2017	RCV001098517.4
Open-angle glaucoma	Uncertain significance (1)	reviewed by expert panel	Aug 7, 2023	RCV003319992.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Aug 07, 2023) C Contributing to aggregate classification	reviewed by expert panel (ClinGen Glaucoma ACMG Specifications v1.1) Method: curation	Open-angle glaucoma (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Glaucoma Variant Curation Expert Panel FDA Recognized Database Accession: SCV004024258.1 First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/54390ffa-8631-4d0f-8a41-69794f4a5f22 Comment: The c.1345G>A variant in MYOC is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 449 (p.Val449Ile). The highest minor … (more) The c.1345G>A variant in MYOC is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 449 (p.Val449Ile). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0002940 (9 alleles out of 30,616), which did not meet the PM2_Supporting allele frequency threshold (<= 0.0001) or the BS1 allele frequency threshold (>= 0.001). The REVEL score = 0.181, 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. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant has not yet been identified in a proband with juvenile or primary open angle glaucoma, only in a participant of the control cohort. Additionally, as PM2_Supporting was not met, PS4 did not apply. In summary, this variant did not meet any criteria, receiving a score of 0 and a classification 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): none. (less)
Uncertain significance (Apr 28, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Glaucoma Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001254887.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 28, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Glaucoma 1, open angle, A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001254888.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)

Comment:

The c.1345G>A variant in MYOC is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 449 (p.Val449Ile). The highest minor allele frequency of this variant was in the South Asian population of gnomAD (v2.1.1) = 0.0002940 (9 alleles out of 30,616), which did not meet the PM2_Supporting allele frequency threshold (<= 0.0001) or the BS1 allele frequency threshold (>= 0.001). The REVEL score = 0.181, 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. There was no functional evidence predicting a damaging or benign impact of this variant on MYOC function. This variant has not yet been identified in a proband with juvenile or primary open angle glaucoma, only in a participant of the control cohort. Additionally, as PM2_Supporting was not met, PS4 did not apply. In summary, this variant did not meet any criteria, receiving a score of 0 and a classification 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): none.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/54390ffa-8631-4d0f-8a41-69794f4a5f22	-	-	-	-

Text-mined citations for rs572512491 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 25, 2023

ClinVar Genomic variation as it relates to human health

NM_000261.2(MYOC):c.1345G>A (p.Val449Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs572512491 ...