NM_000492.3(CFTR):c.3067_3072del (p.Ile1023_Val1024del) AND Cystic fibrosis

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Oct 1, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000046775.14

Allele description [Variation Report for NM_000492.3(CFTR):c.3067_3072del (p.Ile1023_Val1024del)]

NM_000492.3(CFTR):c.3067_3072del (p.Ile1023_Val1024del)

Genes:
CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC111674472:DNase I hypersensitive sites in introns 16 and 17a of CFTR [Gene]
Variant type:
Deletion
Cytogenetic location:
7q31.2
Genomic location:
Preferred name:
NM_000492.3(CFTR):c.3067_3072del (p.Ile1023_Val1024del)
Other names:
CFTR, 3199del6
HGVS:
  • NC_000007.13:g.117250647_117250652del
  • NC_000007.14:g.117610597_117610602del
  • NG_016465.4:g.149814_149819del
  • NG_056128.1:g.3651_3656del
  • NG_056128.2:g.3651_3656del
  • NM_000492.3:c.3067_3072del
  • NP_000483.3:p.Ile1023_Val1024del
  • NP_000483.3:p.Ile1023_Val1024del
  • NP_000483.3:p.Ile1023_Val1024del
  • NP_000483.3:p.Ile1023_Val1024del
  • LRG_663t1:c.3067_3072del
  • LRG_663:g.149814_149819del
  • LRG_663p1:p.Ile1023_Val1024del
  • NC_000007.13:g.117250647_117250652del
  • NC_000007.13:g.117250651_117250656del
  • NC_000007.13:g.117250651_117250656delATAGTG
  • NG_016465.1:g.135635_135640del
  • NM_000492.3:c.3063_3068delAGTGAT
  • NM_000492.3:c.3067_3072delATAGTG
Links:
dbSNP: rs121908767
NCBI 1000 Genomes Browser:
rs121908767
Molecular consequence:
  • NM_000492.3:c.3067_3072del - inframe_deletion - [Sequence Ontology: SO:0001822]

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
SCV000074788Invitaecriteria provided, single submitter
Pathogenic
(Oct 1, 2020)
germlineclinical testing

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

SCV000696944Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Jan 18, 2016)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000886159Mendelicscriteria provided, single submitter
Likely pathogenic
(Nov 5, 2018)
unknownclinical testing

Citation Link,

SCV001169285CFTR-Francecriteria provided, single submitter
Pathogenic
(Jan 29, 2018)
germlinecuration

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

SCV001193959Myriad Women's Health, Inc.criteria provided, single submitter
Pathogenic
(Dec 4, 2019)
unknownclinical testing

PubMed (14)
[See all records that cite these PMIDs]

Citation Link,

SCV001425301Johns Hopkins Genomics, Johns Hopkins Universitycriteria provided, single submitter
Pathogenic
(Mar 4, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedcuration
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Report on the p.Ser489X (p.Ser489*) CFTR mutation, a variant with severe associated phenotype and high prevalence in a Quebec French-Canadian cystic fibrosis patient population.

De Bie I, Agatep R, Scott P, Ruchon A.

Genet Med. 2012 Oct;14(10):883-6. doi: 10.1038/gim.2012.57. Epub 2012 May 24.

PubMed [citation]
PMID:
22627569
See all PubMed Citations (23)

Details of each submission

From Invitae, SCV000074788.6

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

Description

This sequence change deletes 6 nucleotides from exon 19 of the CFTR mRNA (c.3067_3072del). This leads to the deletion of 2 amino acid residues in the CFTR protein (p.Ile1023_Val1024del) but otherwise preserves the integrity of the reading frame. The frequency data for this variant (rs397508492) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported with a pathogenic variant in several individuals with cystic fibrosis (PMID: 7516234, 12394343, 22627569, 15287992) or congenital absence of the vas deferens (PMID: 22020151). In four of these individuals this variant was confirmed to be in trans with the pathogenic variant (PMID: 7516234, 15287992). In the literature, this variant is also known as 3199del6 or 3195del6. ClinVar contains an entry for this variant (Variation ID: 38480). An experimental study did not detect a CFTR transcript in an affected individual who carried both this c.3067_3072del variant and a truncating variant on the opposite allele (PMID: 8707304). However, a CFTR transcript was detected in the parent who only carried the c.3067_3072del variant, raising concerns about the validity of this experimental analysis. No functional investigation into the effect of this variant on protein function has been reported. In summary, this is a rare in-frame deletion that has been observed in trans with two different pathogenic variants in multiple affected individuals, and in combination with pathogenic variants (phase unknown) in several others. For these reasons, this variant has been classified as Pathogenic.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696944.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

Variant summary: The c.3067_3072delATAGTG (a.k.a. 3199del6) in CFTR gene is an in-frame deletion that expected to remove Ile1023 and Val1024 from the CFTR protein. Mutation Taster predicts deleterious outcome. The variant is absent from the large and broad cohorts of the ExAC project. The variant of interest has been identified in multiple affected individuals presented with CF and was referred as causative mutation in peer-reviewed publications. At least one reputable clinical laboratory/diagnostic center classified the variant as Pathogenic. Taking together, the variant was classified as Pathogenic.

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

From Mendelics, SCV000886159.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From CFTR-France, SCV001169285.1

#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 Women's Health, Inc., SCV001193959.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (14)

Description

NM_000492.3(CFTR):c.3067_3072del6(aka 3199del6) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 15371908, 10798368, 12172395, 15371907, 11668613, 8707304, 15371903, 15017334, 15638824, 7516234, 22020151, 18456578, 12394343 and 21679131. Classification of NM_000492.3(CFTR):c.3067_3072del6(aka 3199del6) is based on the following criteria: This is a well-established pathogenic variant in the literature that 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

From Johns Hopkins Genomics, Johns Hopkins University, SCV001425301.1

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

Description

c.3067_3072del has been observed in multiple patients presenting with cystic fibrosis in whom a second disease-associated variant was identified. This variant (rs397508492) is rare (<0.1%) in a large population dataset (gnomAD: 7/251080 total alleles; 0.002788%; no homozygotes). Additionally, seven submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. We consider this variant to be pathogenic.

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

Last Updated: Sep 12, 2021

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