NM_001379270.1(CNGA1):c.253del (p.Leu85fs) AND Retinitis pigmentosa 49

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 22, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000490509.12

Allele description [Variation Report for NM_001379270.1(CNGA1):c.253del (p.Leu85fs)]

NM_001379270.1(CNGA1):c.253del (p.Leu85fs)

Genes:

CNGA1:cyclic nucleotide gated channel subunit alpha 1 [Gene - OMIM - HGNC]
LOC101927157:uncharacterized LOC101927157 [Gene]

Variant type:

Deletion

Cytogenetic location:

4p12

Genomic location:

Preferred name:

NM_001379270.1(CNGA1):c.253del (p.Leu85fs)

HGVS:

NC_000004.12:g.47949867del
NG_009193.1:g.68078del
NM_000087.5:c.253del
NM_001142564.2:c.253del
NM_001375386.1:c.265delC
NM_001379270.1:c.253delMANE SELECT
NP_000078.3:p.Leu85fs
NP_001136036.2:p.Leu85fs
NP_001362315.1:p.Leu89Phefs
NP_001366199.1:p.Leu85fs
NC_000004.11:g.47951884del
NM_000087.3:c.265del
NM_000087.3:c.265delC
NM_001142564.1:c.472del
NM_001142564.1:c.472delG

Protein change:

L85fs

Links:

OMIM: 123825.0006; OMIM: 123825.0009; dbSNP: rs749012133

NCBI 1000 Genomes Browser:

rs749012133

Molecular consequence:

NM_000087.5:c.253del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001142564.2:c.253del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001375386.1:c.265delC - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001379270.1:c.253del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Retinitis pigmentosa 49 (RP49)
Identifiers:: MONDO: MONDO:0013405; MedGen: C3151059; Orphanet: 791; OMIM: 613756

Recent activity

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hypothetical protein Csa_006600 [Cucumis sativus]
hypothetical protein Csa_006600 [Cucumis sativus]
gi|700206774|gb|KGN61893.1||gnl|WGS |CsaV3_2P015670.1.cds1

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000267257	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 18, 2016)	germline	reference population	PubMed (3) [See all records that cite these PMIDs] 23462753, 7479749, 25741868
SCV002521368	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25268133, 23462753, 25741868
SCV003841137	OMIM	no assertion criteria provided	Pathogenic (Feb 23, 2023)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000267257

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 18, 2016)

germline

reference population

PubMed (3)
[See all records that cite these PMIDs]

SCV002521368

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 22, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003841137

OMIM

no assertion criteria provided

Pathogenic
(Feb 23, 2023)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
East Asian	germline	unknown	2	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa.

Dryja TP, Finn JT, Peng YW, McGee TL, Berson EL, Yau KW.

Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10177-81.

PubMed [citation]

PMID:: 7479749
PMCID:: PMC40759

Targeted sequencing of 179 genes associated with hereditary retinal dystrophies and 10 candidate genes identifies novel and known mutations in patients with various retinal diseases.

Chen X, Zhao K, Sheng X, Li Y, Gao X, Zhang X, Kang X, Pan X, Liu Y, Jiang C, Shi H, Chen X, Rong W, Chen LJ, Lai TY, Liu Y, Wang X, Yuan S, Liu Q, Vollrath D, Pang CP, Zhao C.

Invest Ophthalmol Vis Sci. 2013 Mar 1;54(3):2186-97. doi: 10.1167/iovs.12-10967.

PubMed [citation]

PMID:: 23462753

See all PubMed Citations (4)

Details of each submission

From Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267257.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	2	not provided	not provided	reference population	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From 3billion, SCV002521368.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Frameshift: 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. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25268133). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000225315 / PMID: 23462753). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From OMIM, SCV003841137.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 51-year-old Japanese woman (RP#029) and an unrelated 46-year-old Japanese man (RP#094) with retinitis pigmentosa (RP49; 613756), Katagiri et al. (2014) identified homozygosity for a 1-bp deletion (c.265delC, NM_000087) in exon 6 of the CNGA1 gene, causing a frameshift predicted to result in a premature termination codon (Leu89PhefsTer4) with loss of most of the protein structure including all 3 functional domains. A third patient, a 35-year-old Japanese woman (RP#019) was found to be compound heterozygous for the c.265delC mutation and another 1-bp deletion in exon 11 of CNGA1 (c.1429delG; 123825.0007), also causing a frameshift and a premature termination codon (Val477TyrfsTer17), with loss of the sixth transmembrane domain helix, the cGMP-binding site, and the coiled-coil CLZ domain. Her unaffected parents were each heterozygous for 1 of the deletions; parental DNA was unavailable for the other 2 probands. Haplotype analysis showed an identical haplotype for the c.265delC allele in RP#019 and both alleles in RP#029, suggesting a common ancestor for the deletion.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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