NM_001379270.1(CNGA1):c.253del (p.Leu85fs) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 17, 2023
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:: RCV001008796.12

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]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001168594	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jul 19, 2018)	germline	clinical testing	Citation Link,
SCV001578484	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 7479749, 23462753, 25268133, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001168594

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jul 19, 2018)

germline

clinical testing

Citation Link,

SCV001578484

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 17, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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 GeneDx, SCV001168594.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The c.265delC variant in the CNGA1 gene has been reported previously in both the homozygous state and the compound heterozygous state with another CNGA1 variant in association with retinitis pigmentosa (Katagiri et al., 2014). This variant causes a frameshift starting with codon Leucine 89, changes this amino acid to a Phenylalanine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Leu89PhefsX4. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.265delC variant is observed in 26/18870 (0.1378%) alleles from individuals of East Asian background in large population cohorts, with no homozygotes reported (Lek et al., 2016). We interpret c.265delC as a pathogenic variant.

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

From Invitae, SCV001578484.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Leu89Phefs*4) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 225315). This variant is also known as p.Leu158Phefs*4. This premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 23462753, 25268133). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs749012133, gnomAD 0.1%).

#	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		not provided	not provided	not provided	not provided

Last Updated: Jul 23, 2024

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