VCV000548707.18 - ClinVar

NM_001379270.1(CNGA1):c.82C>T (p.Arg28Ter)

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.

(9)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001379270.1(CNGA1):c.82C>T (p.Arg28Ter)

Variation ID: 548707 Accession: VCV000548707.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p12 4: 47952608 (GRCh38) [ NCBI UCSC ] 4: 47954625 (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	Jul 14, 2018	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001379270.1:c.82C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001366199.1:p.Arg28Ter	nonsense
NM_000087.4:c.94C>T
NM_000087.5:c.82C>T	NP_000078.3:p.Arg28Ter	nonsense
NM_001142564.2:c.82C>T	NP_001136036.2:p.Arg28Ter	nonsense
NC_000004.12:g.47952608G>A
NC_000004.11:g.47954625G>A
NG_009193.1:g.65337C>T

... more HGVS ... less HGVS

Protein change

R101*, R28*

Other names

Canonical SPDI

NC_000004.12:47952607:G:A

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

termination codon change; Variation Ontology [ VariO:0309]

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.

0.00040 (A)

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

The Genome Aggregation Database (gnomAD) 0.00006

The Genome Aggregation Database (gnomAD), exomes 0.00007

Exome Aggregation Consortium (ExAC) 0.00008

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Trans-Omics for Precision Medicine (TOPMed) 0.00009

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

Links

dbSNP: rs199636364 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.
CNGA1		-	-	GRCh38 GRCh37	13	497
LOC101927157	-	-	-	GRCh38	-	465

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.
Retinitis pigmentosa 49	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 3, 2022	RCV000662351.5
Retinitis pigmentosa	Pathogenic (1)	no assertion criteria provided	Jun 23, 2019	RCV001002956.1
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Jun 20, 2017	RCV001075248.2
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV001268020.13

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.
Pathogenic (May 28, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 49 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Servicio Extremeño de Salud, Hospital de Mérida Accession: SCV000778497.1 First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018	Comment: This variant, p.Arg101Ter, was found in homozygous state in a Spanish patient with Retinitis pigmentosa and the frequency of the variant in Public databases 1000G, … (more) This variant, p.Arg101Ter, was found in homozygous state in a Spanish patient with Retinitis pigmentosa and the frequency of the variant in Public databases 1000G, ESP, and ExAC is consistent with the mode of inheritance and the variation is considered as pathogenic following ACMG criteria. (less) Clinical Features: Rod-cone dystrophy (present) Indication for testing: Clinical features observed in this individual Age: 50-59 years Sex: female Ethnicity/Population group: Caucasian Geographic origin: Extremadura, Spain, Europe
Pathogenic (Jun 20, 2017)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001240862.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446603.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Rod-cone dystrophy (present) Sex: female
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 49 Affected status: yes Allele origin: germline	3billion Accession: SCV002058710.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:12362048 PMID:12362048 Comment: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more) Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000548707, PMID:12362048). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000068, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Visual impairment (present)
Pathogenic (Jan 14, 2024)	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: SCV001582777.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 7479749‚ 25268133‚ 12362048‚ 30337596 Comment: This sequence change creates a premature translational stop signal (p.Arg32) in the CNGA1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg32) in the CNGA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNGA1 are known to be pathogenic (PMID: 7479749, 25268133). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 12362048, 30337596). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg28* or p.Arg101*. ClinVar contains an entry for this variant (Variation ID: 548707). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV005092904.3 First in ClinVar: Aug 04, 2024 Last updated: Oct 20, 2024	Comment: CNGA1: PVS1, PM3:Strong, PM2 Number of individuals with the variant: 1
Pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001160999.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800746.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001926022.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021

Comment:

This variant, p.Arg101Ter, was found in homozygous state in a Spanish patient with Retinitis pigmentosa and the frequency of the variant in Public databases 1000G, ESP, and ExAC is consistent with the mode of inheritance and the variation is considered as pathogenic following ACMG criteria.

Comment:

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000548707, PMID:12362048). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000068, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

This sequence change creates a premature translational stop signal (p.Arg32*) in the CNGA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CNGA1 are known to be pathogenic (PMID: 7479749, 25268133). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 12362048, 30337596). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg28* or p.Arg101*. ClinVar contains an entry for this variant (Variation ID: 548707). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
termination codon change (VariO:0309)			Servicio Extremeño de Salud, Hospital de Mérida Accession: SCV000778497.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A new approach based on targeted pooled DNA sequencing identifies novel mutations in patients with Inherited Retinal Dystrophies.	Ezquerra-Inchausti M	Scientific reports	2018	PMID: 30337596
Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.	Katagiri S	PloS one	2014	PMID: 25268133
Novel homozygous mutation in the alpha subunit of the rod cGMP gated channel (CNGA1) in two Spanish sibs affected with autosomal recessive retinitis pigmentosa.	Paloma E	Journal of medical genetics	2002	PMID: 12362048
Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.	Dryja TP	Proceedings of the National Academy of Sciences of the United States of America	1995	PMID: 7479749

Text-mined citations for rs199636364 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001379270.1(CNGA1):c.82C>T (p.Arg28Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199636364 ...