NM_000492.4(CFTR):c.3222T>A (p.Phe1074Leu) AND Cystic fibrosis

Clinical significance:Likely pathogenic (Last evaluated: Dec 21, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000046829.5

Allele description [Variation Report for NM_000492.4(CFTR):c.3222T>A (p.Phe1074Leu)]

NM_000492.4(CFTR):c.3222T>A (p.Phe1074Leu)

Genes:
CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
LOC111674472:DNase I hypersensitive sites in introns 16 and 17a of CFTR [Gene]
Variant type:
single nucleotide variant
Cytogenetic location:
7q31.2
Genomic location:
Preferred name:
NM_000492.4(CFTR):c.3222T>A (p.Phe1074Leu)
HGVS:
  • NC_000007.14:g.117611663T>A
  • NG_016465.4:g.150880T>A
  • NG_056128.1:g.4717T>A
  • NG_056128.2:g.4717T>A
  • NM_000492.3:c.3222T>A
  • NM_000492.4:c.3222T>AMANE SELECT
  • NP_000483.3:p.Phe1074Leu
  • NP_000483.3:p.Phe1074Leu
  • LRG_663t1:c.3222T>A
  • LRG_663:g.150880T>A
  • LRG_663p1:p.Phe1074Leu
  • NC_000007.13:g.117251717T>A
Protein change:
F1074L
Links:
PharmGKB: 1449191752PA165950341; dbSNP: rs186045772
NCBI 1000 Genomes Browser:
rs186045772
Molecular consequence:
  • NM_000492.3:c.3222T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000492.4:c.3222T>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000220505Counsylcriteria provided, single submitter
Likely pathogenic
(Jul 11, 2014)
unknownliterature only

PubMed (12)
[See all records that cite these PMIDs]

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

Citation Link,

SCV001361660Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely pathogenic
(Dec 21, 2020)
germlineclinical testing

PubMed (17)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Is early identification of asymptomatic infants with 'mild' CFTR genotypes clinically useful?

Colombo C, Costantini D, Russo MC, Claut L, Porcaro L, Nobili R.

Acta Paediatr. 2007 Mar;96(3):477-9. No abstract available.

PubMed [citation]
PMID:
17407489

Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening.

Kalid O, Mense M, Fischman S, Shitrit A, Bihler H, Ben-Zeev E, Schutz N, Pedemonte N, Thomas PJ, Bridges RJ, Wetmore DR, Marantz Y, Senderowitz H.

J Comput Aided Mol Des. 2010 Dec;24(12):971-91. doi: 10.1007/s10822-010-9390-0. Epub 2010 Oct 26.

PubMed [citation]
PMID:
20976528
PMCID:
PMC4010227
See all PubMed Citations (19)

Details of each submission

From Counsyl, SCV000220505.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (12)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361660.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (17)

Description

Variant summary: CFTR c.3222T>A (p.Phe1074Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-06 in 253492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3222T>A, has been reported in cis with 5T allele in individuals affected with Non-classic Cystic Fibrosis (Casals_1997, Casals_2000). In those three patients, authors did not find a pathogenic variant in the second allele, however in the fourth patient p.G551D (a known pathogenic variant) was detected in other allele. These data indicate that the variant may be associated with disease. At least one publication reports that this variant leads to impaired chloride transport and processing (Van Goor_2013, Prins_2020), consistent with the mild CF disease associated with this variant. Three submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic n=1, pathogenic n=1, drug reponse n=1 (expert panel/PharmGKB)). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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

Last Updated: Jun 14, 2021

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