NM_000492.4(CFTR):c.3883_3886del (p.Ile1295fs) AND Cystic fibrosis

Germline classification:: Pathogenic (6 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:: RCV000047015.18

Allele description [Variation Report for NM_000492.4(CFTR):c.3883_3886del (p.Ile1295fs)]

NM_000492.4(CFTR):c.3883_3886del (p.Ile1295fs)

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.3883_3886del (p.Ile1295fs)

Other names:

4010del4

HGVS:

NC_000007.14:g.117652847ATTT[1]
NG_016465.4:g.192064ATTT[1]
NM_000492.4:c.3883_3886delMANE SELECT
NP_000483.3:p.Ile1295fs
LRG_663t1:c.3883_3886del
LRG_663:g.192064ATTT[1]
NC_000007.13:g.117292900_117292903del
NC_000007.13:g.117292901ATTT[1]
NM_000492.3:c.3882_3885delTATT
NM_000492.3:c.3883_3886del
NM_000492.3:c.3883_3886delATTT
p.Ile1295PhefsX32

Protein change:

I1295fs

Links:

OMIM: 602421.0089; dbSNP: rs387906373

NCBI 1000 Genomes Browser:

rs387906373

Molecular consequence:

NM_000492.4:c.3883_3886del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

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

Recent activity

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PREDICTED: Homo sapiens cilia and flagella associated protein 52 (CFAP52), trans...
PREDICTED: Homo sapiens cilia and flagella associated protein 52 (CFAP52), transcript variant X4, mRNA
gi|2217310173|ref|XM_017024227.2|

Nucleotide
cilia- and flagella-associated protein 52 isoform X2 [Homo sapiens]
cilia- and flagella-associated protein 52 isoform X2 [Homo sapiens]
gi|2462553332|ref|XP_054171147.1|

Protein
tail family protein [Lactococcus phage 50902]
tail family protein [Lactococcus phage 50902]
gi|1877793050|ref|YP_009900713.1|

Protein
Astragalus camptodontus isolate ACa ribulose-1,5-bisphosphate carboxylase/oxygen...
Astragalus camptodontus isolate ACa ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit (rbcL) gene, partial cds; chloroplast
gi|1395440734|gb|MF044417.1|

Nucleotide
RecName: Full=Liprin-alpha-3; AltName: Full=Protein tyrosine phosphatase recepto...
RecName: Full=Liprin-alpha-3; AltName: Full=Protein tyrosine phosphatase receptor type f polypeptide-interacting protein alpha-3; Short=PTPRF-interacting protein alpha-3
gi|42558941|sp|O75145.3|LIPA3_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000027817	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 1994)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000075028	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 1695717, 7691345, 9725922, 28546993, 28492532
SCV000245947	CFTR2 - CFTR2	reviewed by expert panel (Sosnay PR et al. (Nat Genet 2013))	Pathogenic (Mar 17, 2017)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001169349	CFTR-France	criteria provided, single submitter (Claustres M et al. (Hum Mutat 2017))	Pathogenic (Jan 29, 2018)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV002574087	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 5, 2022)	unknown	curation	PubMed (1) [See all records that cite this PMID]
SCV002623842	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Aug 13, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26255232, 28546993, 32539862, 7520798 Citation Link

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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	research, curation
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

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 (11)

Details of each submission

From OMIM, SCV000027817.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a patient of Arab origin with cystic fibrosis (CF; 219700), Shoshani et al. (1994) detected a 4-bp deletion in the CFTR gene, TATT, at position 4010 of the coding sequence using direct sequencing of exon 21. This frameshift mutation is expected to create a termination codon (TAG) 34 amino acids downstream of the mutation. This alteration is likely to be a disease-causing mutation since it is predicted to create a truncated polypeptide that lacks the second ATP binding domain. The patient inherited this deletion from her father. The CFTR chromosome carries the D121 haplotype. Her other CFTR chromosome has the asn1303-to-lys mutation (602421.0032).

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000075028.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Ile1295Phefs*32) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 28546993). ClinVar contains an entry for this variant (Variation ID: 53838). For these reasons, this variant has been classified as 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

From CFTR2 - CFTR2, SCV000245947.2

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

#	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 CFTR-France, SCV001169349.1

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

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV002574087.1

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

Description

This variant was identified in 1 patient 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, PM2_SUP, PM3_STR

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

From Ambry Genetics, SCV002623842.2

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

Description

The c.3883_3886delATTT pathogenic mutation, located in coding exon 24 of the CFTR gene, results from a deletion of 4 nucleotides at nucleotide positions 3883 to 3886, causing a translational frameshift with a predicted alternate stop codon (p.I1295Ffs*32). This variant (also referred to as 4010delTATT and 4015delATTT) was initially detected in an Israeli individual with cystic fibrosis (CF) and a second CFTR mutation reportedly on the opposite allele (Shoshani T et al. Hum. Mol. Genet., 1994 Apr;3:657-8). This mutation has subsequently also been reported in additional patients with CF with second mutations identified (Zomer-van Ommen DD et al. J. Cyst. Fibros. 2016 Mar;15(2):158-62; Behar DM et al. Mol Genet Genomic Med. 2017 May;5(3):223-236; Liu K et al. Orphanet J Rare Dis. 2020 Jun;15(1):150). 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.

#	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: Sep 29, 2024

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