NM_000492.4(CFTR):c.273+3A>C AND Cystic fibrosis

Clinical significance:Pathogenic (Last evaluated: Mar 17, 2017)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000029501.7

Allele description [Variation Report for NM_000492.4(CFTR):c.273+3A>C]

NM_000492.4(CFTR):c.273+3A>C

Gene:
CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7q31.2
Genomic location:
Preferred name:
NM_000492.4(CFTR):c.273+3A>C
Other names:
405+3A->C
HGVS:
  • NC_000007.14:g.117509145A>C
  • NG_016465.4:g.48362A>C
  • NG_062452.1:g.783A>C
  • NM_000492.4:c.273+3A>CMANE SELECT
  • LRG_663t1:c.273+3A>C
  • LRG_663:g.48362A>C
  • NC_000007.13:g.117149199A>C
  • NM_000492.3:c.273+3A>C
Links:
dbSNP: rs74467662
NCBI 1000 Genomes Browser:
rs74467662
Molecular consequence:
  • NM_000492.4:c.273+3A>C - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Cystic fibrosis (CF)
Synonyms:
Mucoviscidosis
Identifiers:
MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000052152Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Jun 28, 2019)
germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

Citation Link,

SCV000245989CFTR2 - CFTR2reviewed by expert panel
Pathogenic
(Mar 17, 2017)
germlineresearch

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

Citation Link,

SCV001193953Myriad Women's Health, Inc.criteria provided, single submitter
Likely pathogenic
(Dec 4, 2019)
unknownclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedresearch
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel.

Watson MS, Cutting GR, Desnick RJ, Driscoll DA, Klinger K, Mennuti M, Palomaki GE, Popovich BW, Pratt VM, Rohlfs EM, Strom CM, Richards CS, Witt DR, Grody WW.

Genet Med. 2004 Sep-Oct;6(5):387-91. No abstract available. Erratum in: Genet Med. 2004 Nov-Dec;6(6):548. Genet Med. 2005 Apr;7(4):286.

PubMed [citation]
PMID:
15371902
PMCID:
PMC3110945

Novel CFTR mutations in black cystic fibrosis patients.

Feuillet-Fieux MN, Ferrec M, Gigarel N, Thuillier L, Sermet I, Steffann J, Lenoir G, Bonnefont JP.

Clin Genet. 2004 Apr;65(4):284-7.

PubMed [citation]
PMID:
15025720
See all PubMed Citations (14)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052152.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

Variant summary: CFTR c.273+3A>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 2/4 computational tools predict the variant weakens/abolishes a 5' splicing donor site. In support of the predicted effect on splicing, Macek et al points out that cytosine is the least common nucleotide at the +3 position of splice-donor sites, and that mutations at this location have been reported to cause aberrant RNA splicing (Macek_1997). However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250744 control chromosomes (gnomAD and Macek_1997). In the literature, the variant has been reported in several African American patients affected with Cystic Fibrosis (CF) (e.g. Macek_1997, Watson_2004). In addition, the CFTR2 database reports 10 patients with this variant, stating that this variant causes CF when combined with another CF-causing variant (average sweat chloride levels in patients harboring this variant was found to be 109 mEq/L and 100% of these patients were pancreatic insufficient). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other submitters, including an expert panel (CFTR2), have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

From CFTR2 - CFTR2, SCV000245989.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Myriad Women's Health, Inc., SCV001193953.2

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

Description

NM_000492.3(CFTR):c.273+3A>C(aka 405+3A>C) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 9150159 and 11388756. Classification of NM_000492.3(CFTR):c.273+3A>C(aka 405+3A>C) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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

Last Updated: Nov 27, 2021

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