NM_000492.4(CFTR):c.3368-2A>T AND Cystic fibrosis

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jun 19, 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:: RCV000409745.5

Allele description [Variation Report for NM_000492.4(CFTR):c.3368-2A>T]

NM_000492.4(CFTR):c.3368-2A>T

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.3368-2A>T

HGVS:

NC_000007.14:g.117614611A>T
NG_016465.4:g.153828A>T
NM_000492.4:c.3368-2A>TMANE SELECT
LRG_663t1:c.3368-2A>T
LRG_663:g.153828A>T
NC_000007.13:g.117254665A>T
NM_000492.3:c.3368-2A>T

Links:

dbSNP: rs755416052

NCBI 1000 Genomes Browser:

rs755416052

Molecular consequence:

NM_000492.4:c.3368-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000486891	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Sep 1, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV002612791	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 26, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004020661	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jun 19, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15858154, 17890437, 11668613, 35934641 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000486891

Counsyl

criteria provided, single submitter

(Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))

Likely pathogenic
(Sep 1, 2016)

unknown

clinical testing

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

mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf,

Citation Link,

SCV002612791

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 26, 2017)

germline

clinical testing

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

Citation Link,

SCV004020661

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jun 19, 2023)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	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

Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum.

Schrijver I, Ramalingam S, Sankaran R, Swanson S, Dunlop CL, Keiles S, Moss RB, Oehlert J, Gardner P, Wassman ER, Kammesheidt A.

J Mol Diagn. 2005 May;7(2):289-99.

PubMed [citation]

PMID:: 15858154
PMCID:: PMC1867528

Scanning the cystic fibrosis transmembrane conductance regulator gene using high-resolution DNA melting analysis.

Montgomery J, Wittwer CT, Kent JO, Zhou L.

Clin Chem. 2007 Nov;53(11):1891-8. Epub 2007 Sep 21.

PubMed [citation]

PMID:: 17890437

See all PubMed Citations (4)

Details of each submission

From Counsyl, SCV000486891.2

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

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

From Ambry Genetics, SCV002612791.2

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

Description

The c.3368-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 21 in the CFTR gene. This mutation was identified in an individual with cystic fibrosis with elevated sweat chloride levels and meconium ileus at birth, reduced lung function, Pseudomonas infection, pancreatic insufficiency, and a second CFTR alteration (Wong LJ et al. Hum. Mutat., 2001 Oct;18:296-307). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004020661.1

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

Description

Variant summary: CFTR c.3368-2A>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 3' acceptor site, and two predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250888 control chromosomes (gnomAD v2.1, Exomes dataset). c.3368-2A>T has been reported in the literature in individuals affected with Cystic Fibrosis (e.g., Wong_2001, Schrijver_2005, Montgomery_2007, Zahav_2023). These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17890437, 15858154, 11668613, 35934641). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic (n = 1) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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: May 1, 2024

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