NM_000492.3(CFTR):c.4004T>C (p.Leu1335Pro) AND not specified

Clinical significance:Pathogenic (Last evaluated: Mar 22, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000492.3(CFTR):c.4004T>C (p.Leu1335Pro)]

NM_000492.3(CFTR):c.4004T>C (p.Leu1335Pro)

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000492.3(CFTR):c.4004T>C (p.Leu1335Pro)
  • NC_000007.14:g.117664728T>C
  • NG_016465.4:g.203945T>C
  • NM_000492.3:c.4004T>C
  • NP_000483.3:p.Leu1335Pro
  • LRG_663t1:c.4004T>C
  • LRG_663:g.203945T>C
  • LRG_663p1:p.Leu1335Pro
  • NC_000007.13:g.117304782T>C
Protein change:
dbSNP: rs397508658
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000492.3:c.4004T>C - missense variant - [Sequence Ontology: SO:0001583]


MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000919159Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
(Mar 22, 2018)
germlineclinical testing

PubMed (10)
[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



Does the Macroduct collection system reliably define sweat chloride concentration in subjects with intermediate results?

Rose JB, Ellis L, John B, Martin S, Gonska T, Solomon M, Tullis E, Corey M, Adeli K, Durie PR.

Clin Biochem. 2009 Aug;42(12):1260-4. doi: 10.1016/j.clinbiochem.2009.05.001. Epub 2009 May 13.

PubMed [citation]

Targeted sequencing reveals complex, phenotype-correlated genotypes in cystic fibrosis.

Ivanov M, Matsvay A, Glazova O, Krasovskiy S, Usacheva M, Amelina E, Chernyak A, Ivanov M, Musienko S, Prodanov T, Kovalenko S, Baranova A, Khafizov K.

BMC Med Genomics. 2018 Feb 13;11(Suppl 1):13. doi: 10.1186/s12920-018-0328-z.

PubMed [citation]
See all PubMed Citations (10)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919159.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)


Variant summary: CFTR c.4004T>C (p.Leu1335Pro) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276844 control chromosomes. c.4004T>C has been reported in the literature in individuals affected with Cystic Fibrosis, but in most of these cases without a second allele specified or sweat chloride concentrations. Two reported pancreatic sufficient CF patients were compound heterozygous for the variant and the deltaF508 pathogenic allele with elevated sweat chloride levels (Rose 2009, Ivanov 2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. However, the CFTR2 database classifies the variant as CF-causing based on 18 patients in the database with an average sweat chloride level of 82 mEq/L. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Aug 27, 2021

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