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NM_001298.3(CNGA3):c.101+1G>A AND Achromatopsia 2

Germline classification:
Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:
Apr 4, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV000190571.22

Allele description [Variation Report for NM_001298.3(CNGA3):c.101+1G>A]

NM_001298.3(CNGA3):c.101+1G>A

Gene:
CNGA3:cyclic nucleotide gated channel subunit alpha 3 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q11.2
Genomic location:
Preferred name:
NM_001298.3(CNGA3):c.101+1G>A
HGVS:
  • NC_000002.12:g.98370077G>A
  • NG_009097.1:g.28923G>A
  • NM_001079878.2:c.101+1G>A
  • NM_001298.3:c.101+1G>AMANE SELECT
  • NC_000002.11:g.98986540G>A
  • NM_001298.2:c.101+1G>A
Links:
dbSNP: rs147118493
NCBI 1000 Genomes Browser:
rs147118493
Molecular consequence:
  • NM_001079878.2:c.101+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001298.3:c.101+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
Observations:
1

Condition(s)

Name:
Achromatopsia 2 (ACHM2)
Synonyms:
Colorblindness, total; Rod monochromatism 2; Rod monochromacy 2
Identifiers:
MONDO: MONDO:0009003; MedGen: C1857618; Orphanet: 49382; OMIM: 216900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000245590Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq
criteria provided, single submitter

(LMM Criteria)
Likely pathogenic
(Oct 20, 2014)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000914946Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)
Uncertain significance
(Nov 15, 2018)
germlineclinical testing

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

Citation Link,

SCV001142320Reproductive Health Research and Development, BGI Genomics
no assertion criteria provided
Pathogenic
(Jan 6, 2020)
germlinecuration

SCV001524041Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Jul 9, 2020)
unknownclinical testing

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

SCV003826890Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Sep 20, 2022)
germlineclinical testing

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

SCV004810153Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Apr 4, 2024)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

CNGA3 mutations in hereditary cone photoreceptor disorders.

Wissinger B, Gamer D, J├Ągle H, Giorda R, Marx T, Mayer S, Tippmann S, Broghammer M, Jurklies B, Rosenberg T, Jacobson SG, Sener EC, Tatlipinar S, Hoyng CB, Castellan C, Bitoun P, Andreasson S, Rudolph G, Kellner U, Lorenz B, Wolff G, Verellen-Dumoulin C, et al.

Am J Hum Genet. 2001 Oct;69(4):722-37. Epub 2001 Aug 30.

PubMed [citation]
PMID:
11536077
PMCID:
PMC1226059

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020
See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq, SCV000245590.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

The c.101+1G>A variant in CNGA3 has not been previously reported in individuals with achromatopsia, but has been identified in 0.08% (7/8600) of European American chromosomes and 0.02% (1/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs147118493). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Complete loss of CNGA3 function is an established disease mechanism in individuals with achromatopsia (Wissinger 2001). In summary, although additional studies are required to fully establish its clinical significance, the c.101+1G>A variant is likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Illumina Laboratory Services, Illumina, SCV000914946.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

The CNGA3 c.101+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.101+1G>A variant has been reported in one study and found in three unrelated individuals from consanguineous families affected with achromatopsia in a homozygous state (Abdelkader et al. 2018). Two of these individuals were also homozygous for a stop-gained variant, p.Arg221Ter. Control data are unavailable for this variant, which is reported at a frequency of 0.005956 in the Ashkenazi Jewish population of the Genome Aggregation Database. Due to the potential impact of splice donor variants and the limited evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for achromatopsia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Reproductive Health Research and Development, BGI Genomics, SCV001142320.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

NG_009097.1(NM_001298.2):c.101+1G>A in the CNGA3 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The CNGA3 c.101+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant has been reported in one study and found in three unrelated individuals from consanguineous families affected with achromatopsia in a homozygous state (PMID: 30289319). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM3_Supporting, PP4.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Baylor Genetics, SCV001524041.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Revvity Omics, Revvity, SCV003826890.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004810153.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2024