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NM_000492.4(CFTR):c.3773dup (p.Leu1258fs) AND Cystic fibrosis

Germline classification:
Pathogenic (7 submissions)
Last evaluated:
Mar 17, 2017
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV000046980.24

Allele description [Variation Report for NM_000492.4(CFTR):c.3773dup (p.Leu1258fs)]

NM_000492.4(CFTR):c.3773dup (p.Leu1258fs)

Gene:
CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
7q31.2
Genomic location:
Preferred name:
NM_000492.4(CFTR):c.3773dup (p.Leu1258fs)
Other names:
3905insT; p.Leu1258Phefs*7
HGVS:
  • NC_000007.13:g.117282541_117282542insT
  • NC_000007.14:g.117642493dup
  • NG_016465.4:g.181710dup
  • NM_000492.4:c.3773dupMANE SELECT
  • NP_000483.3:p.Leu1258fs
  • NP_000483.3:p.Leu1258fs
  • LRG_663t1:c.3773dup
  • LRG_663:g.181710dup
  • LRG_663p1:p.Leu1258fs
  • NC_000007.13:g.117282541_117282542insT
  • NC_000007.13:g.117282547dup
  • NC_000007.13:g.117282547dup
  • NC_000007.13:g.117282547dupT
  • NG_016465.1:g.167531_167532insT
  • NM_000492.3:c.3773dup
  • NM_000492.3:c.3773dupT
  • p.Leu1258PhefsX7
Protein change:
L1258fs
Links:
dbSNP: rs121908789
NCBI 1000 Genomes Browser:
rs121908789
Molecular consequence:
  • NM_000492.4:c.3773dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000071482CFTR2 - CFTR2
reviewed by expert panel

(Sosnay PR et al. (Nat Genet 2013))
Pathogenic
(Mar 17, 2017)
germlineresearch

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

Citation Link,

SCV000074993Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 31, 2024)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001169354CFTR-France
criteria provided, single submitter

(Claustres M et al. (Hum Mutat 2017))
Pathogenic
(Jan 29, 2018)
germlinecuration

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

SCV001194206Myriad Genetics, Inc.
criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))
Pathogenic
(Dec 9, 2019)
unknownclinical testing

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

Citation Link,

SCV001449486Johns Hopkins Genomics, Johns Hopkins University
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 11, 2020)
germlineclinical testing

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

SCV002574065Institute of Human Genetics, University of Leipzig Medical Center
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Sep 5, 2022)
unknowncuration

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

SCV002620760Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(May 30, 2023)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedresearch, curation
not providedunknownyes3not providednot providednot providednot providedcuration
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.

Cutting GR, Kasch LM, Rosenstein BJ, Zielenski J, Tsui LC, Antonarakis SE, Kazazian HH Jr.

Nature. 1990 Jul 26;346(6282):366-9.

PubMed [citation]
PMID:
1695717

Molecular basis of defective anion transport in L cells expressing recombinant forms of CFTR.

Yang Y, Devor DC, Engelhardt JF, Ernst SA, Strong TV, Collins FS, Cohn JA, Frizzell RA, Wilson JM.

Hum Mol Genet. 1993 Aug;2(8):1253-61.

PubMed [citation]
PMID:
7691345
See all PubMed Citations (13)

Details of each submission

From CFTR2 - CFTR2, SCV000071482.4

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

From Invitae, SCV000074993.10

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Leu1258Phefs*7) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs796566397, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with cystic fibrosis (PMID: 19724303, 21520337, 23974870). This variant is also known as 3905insT. ClinVar contains an entry for this variant (Variation ID: 38726). For these reasons, this variant has been classified as Pathogenic.

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

From CFTR-France, SCV001169354.1

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

From Myriad Genetics, Inc., SCV001194206.2

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

Description

NM_000492.3(CFTR):c.3773dupT(L1258Ffs*7, aka 3905insT) is classified as pathogenic in the context of cystic fibrosis and is associated with classic disease. Sources cited for classification include the following: PMID 19724303 and 23974870. Classification of NM_000492.3(CFTR):c.3773dupT(L1258Ffs*7, aka 3905insT) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. 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

From Johns Hopkins Genomics, Johns Hopkins University, SCV001449486.1

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

Description

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002574065.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedcuration PubMed (1)

Description

This variant was identified in 3 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1_STR, PS3_MOD, PM2_SUP, PM3_STR, PP4

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot provided3not providednot providednot provided

From Ambry Genetics, SCV002620760.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The c.3773dupT pathogenic mutation (also known as c.3773_3774insT and 3905insT), located in coding exon 23 of the CFTR gene, results from a duplication of T at nucleotide position 3773, causing a translational frameshift with a predicted alternate stop codon (p.L1258Ffs*7). This mutation was described in 30 compound heterozygous individuals with cystic fibrosis characterized by elevated sweat chloride levels, failure to thrive, pancreatic insufficiency, and progressively decreasing lung function (Schibler A et al. Eur. Respir. J., 2001 Jun;17:1181-6). Immunocytochemical studies demonstrated that this alteration significantly reduces the amount of mature CFTR protein found in the apical membranes of nasal epithelia (Sanz J et al. Eur. J. Hum. Genet., 2010 Feb;18:212-7). This mutation is associated with elevated sweat chloride levels and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Aug 4, 2024