NM_000492.4(CFTR):c.3222T>A (p.Phe1074Leu) AND not provided

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 23, 2018)

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:
RCV000522824.1

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)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000617533GeneDxcriteria provided, single submitter
Pathogenic
(Jul 13, 2017)
germlineclinical testing

Citation Link,

SCV000861385EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Likely pathogenic
(May 23, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod

Details of each submission

From GeneDx, SCV000617533.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The F1074L pathogenic variant in the CFTR gene has been reported previously in cis with the 5T allele in siblings with a mild cystic fibrosis phenotype, but no other variant was found on the opposite CFTR allele (Casals et al., 1997). The F1074L variant has also been reported in cis with the 5T allele and phase unknown with the G551D variant in an individual with congenital bilateral absence of the vas deferens (Casals et al., 2000). Functional studies demonstrate that F1074L is associated with reduced chloride transport (Van Goor et al., 2014). The F1074L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F1074L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. The F1074L variant is reported in the CFTR2 database as being associated with varying consequences. Missense variants in nearby residues (G1069R, R1070Q, R1070W, L1077P) have been reported in the Human Gene Mutation Database in association with cystic fibrosis (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret F1074L as a pathogenic variant.

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

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000861385.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

Last Updated: Jun 14, 2021

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