VCV001056891.8 - ClinVar

NM_001298.3(CNGA3):c.1537G>A (p.Gly513Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001298.3(CNGA3):c.1537G>A (p.Gly513Arg)

Variation ID: 1056891 Accession: VCV001056891.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q11.2 2: 98396707 (GRCh38) [ NCBI UCSC ] 2: 99013170 (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	Apr 13, 2021	Feb 20, 2024	Feb 28, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001298.3:c.1537G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001289.1:p.Gly513Arg	missense
NM_001079878.2:c.1483G>A	NP_001073347.1:p.Gly495Arg	missense
NC_000002.12:g.98396707G>A
NC_000002.11:g.99013170G>A
NG_009097.1:g.55553G>A

... more HGVS ... less HGVS

Protein change

G495R, G513R

Other names

Canonical SPDI

NC_000002.12:98396706:G:A

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.

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

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Links

dbSNP: rs764918448 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.
CNGA3		-	-	GRCh38 GRCh37	713	732

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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Feb 28, 2022	RCV001365786.7
Achromatopsia 2	Likely pathogenic (1)	no assertion criteria provided	Apr 15, 2021	RCV001729857.1

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.
Likely pathogenic (Feb 28, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001562068.5 First in ClinVar: Apr 13, 2021 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 11536077‚ 26992781 Comment: In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more) In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly513 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been observed in individuals with CNGA3-related conditions (PMID: 11536077), which suggests that this may be a clinically significant amino acid residue. 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 CNGA3 protein function. ClinVar contains an entry for this variant (Variation ID: 1056891). This missense change has been observed in individuals with clinical features of achromatopsia and/or cone-rod dystrophy (PMID: 26992781; Invitae). This variant is present in population databases (rs764918448, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 513 of the CNGA3 protein (p.Gly513Arg). (less)
Likely pathogenic (Apr 15, 2021)	no assertion criteria provided Method: research	Achromatopsia 2 Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, Institute for Ophthalmic Research Accession: SCV001571303.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021

Comment:

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly513 amino acid residue in CNGA3. Other variant(s) that disrupt this residue have been observed in individuals with CNGA3-related conditions (PMID: 11536077), which suggests that this may be a clinically significant amino acid residue. 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 CNGA3 protein function. ClinVar contains an entry for this variant (Variation ID: 1056891). This missense change has been observed in individuals with clinical features of achromatopsia and/or cone-rod dystrophy (PMID: 26992781; Invitae). This variant is present in population databases (rs764918448, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 513 of the CNGA3 protein (p.Gly513Arg).

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
Molecular genetics of cone-rod dystrophy in Chinese patients: New data from 61 probands and mutation overview of 163 probands.	Huang L	Experimental eye research	2016	PMID: 26992781
CNGA3 mutations in hereditary cone photoreceptor disorders.	Wissinger B	American journal of human genetics	2001	PMID: 11536077

Text-mined citations for rs764918448 ...

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 Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_001298.3(CNGA3):c.1537G>A (p.Gly513Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs764918448 ...