NM_000492.4(CFTR):c.1054C>T (p.Arg352Trp) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Mar 23, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000506190.7

Allele description [Variation Report for NM_000492.4(CFTR):c.1054C>T (p.Arg352Trp)]

NM_000492.4(CFTR):c.1054C>T (p.Arg352Trp)

Gene:
CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7q31.2
Genomic location:
Preferred name:
NM_000492.4(CFTR):c.1054C>T (p.Arg352Trp)
HGVS:
  • NC_000007.14:g.117540284C>T
  • NG_016465.4:g.79501C>T
  • NM_000492.3:c.1054C>T
  • NM_000492.4:c.1054C>TMANE SELECT
  • NP_000483.3:p.Arg352Trp
  • NP_000483.3:p.Arg352Trp
  • LRG_663t1:c.1054C>T
  • LRG_663:g.79501C>T
  • LRG_663p1:p.Arg352Trp
  • NC_000007.13:g.117180338C>T
Protein change:
R352W
Links:
dbSNP: rs193922497
NCBI 1000 Genomes Browser:
rs193922497
Molecular consequence:
  • NM_000492.3:c.1054C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000492.4:c.1054C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000052119Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Mar 23, 2021)
germlineclinical testing

PubMed (16)
[See all records that cite these PMIDs]

Citation Link,

SCV000603070ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(Dec 10, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum.

Schrijver I, Ramalingam S, Sankaran R, Swanson S, Dunlop CL, Keiles S, Moss RB, Oehlert J, Gardner P, Wassman ER, Kammesheidt A.

J Mol Diagn. 2005 May;7(2):289-99.

PubMed [citation]
PMID:
15858154
PMCID:
PMC1867528

A 10-year large-scale cystic fibrosis carrier screening in the Italian population.

Picci L, Cameran M, Marangon O, Marzenta D, Ferrari S, Frigo AC, Scarpa M.

J Cyst Fibros. 2010 Jan;9(1):29-35. doi: 10.1016/j.jcf.2009.10.003. Epub 2009 Nov 7.

PubMed [citation]
PMID:
19897426
See all PubMed Citations (16)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052119.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (16)

Description

Variant summary: CFTR c.1054C>T (p.Arg352Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 251136 control chromosomes, predominantly at a frequency of 0.003 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00041 vs 0.013), allowing no conclusion about variant significance. c.1054C>T has been reported in the literature in both asymptomatic individuals and subjects diagnosed with multiple CFTR-related phenotypes, including congenital bilateral absence of the vas deferens (CBAVD) and cystic fibrosis (CF). The variant has been reported in compound heterozygosity with the severe pathogenic variant p.Phe508del in individuals diagnosed with CBAVD (e.g. Schwarz_2009, Picci_2010) and in patients followed after a positive newborn screening test, but whom did not meet diagnostic criteria for a diagnosis of CF (e.g. Lilley_2010, Catellani_2016). These data suggest that the variant could be a "mild" mutation, which when combined with a more severe mutation can contribute to less severe CFTR-related phenotypes. c.1054C>T has also been reported in multiple CF patients, however without a second mutation and/or other clinical details available (e.g. Kavanakis_2003, Schrijver_2005, Ciminelli_2007, Giusti_2007, Kharazzi_2015). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence indicating that the variant, when expressed in-vitro in combination with the p.Phe508del mutation, results in approximately 12% of normal CFTR activity (e.g. McCague_2019). In addition, other functional studies investigating the Arg352 residue have reported that this region is important for stabilizing the channel's tertiary structure and predict that mutations in this amino acid may have a functional impact on the protein (e.g. Guinamard_1999, Cui_2008). A different amino acid substitution at this residue, p.Arg352Gln, has been classified by our laboratory as pathogenic. The CFTR2 database reports that this variant has varying consequences and that when combined with another CF-causing variant, some patients have CF, while others do not. Five other ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments (likely benign, n=1; VUS, n=3; likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603070.3

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

Description

The CFTR c.1054C>T; p.Arg352Trp variant (rs193922497) is reported in individuals with cystic fibrosis (CF) (Schrijver 2005), mildly elevated sweat chloride (McGinniss 2005), and congenital absence of the vas deferens (CBAVD) (Picci 2010). In an individual with CBAVD, this variant was reported in trans to the pathogenic p.Phe508del variant (Picci 2010). Further, in testing performed at ARUP Laboratories, the p.Arg352Trp variant has been observed in multiple individuals with CFTR-related disorders that carry a second pathogenic variant, though affected individuals primarily exhibit mild forms of disease instead of classic CF. This variant is reported in ClinVar (Variation ID: 35816) and it is found in the Latino population with an allele frequency of 0.3% (105/35414 alleles) in the Genome Aggregation Database. The arginine at residue 352 is highly conserved, computational algorithms (PolyPhen-2, SIFT) predict that the variant is deleterious, and functional analyses report chloride channel activity of 11% of wildtype (CFTR2 database). Additionally, another variant in the same codon, p.Arg352Gln, is considered pathogenic (Sosnay 2013). Based on available information, the variant is classified as likely pathogenic. References: CFTR2 database: https://cftr2.org McGinniss M et al. Extensive sequencing of the CFTR gene: lessons learned from the first 157 patient samples. Hum Genet. 2005 Dec; 118(3-4):331-8. Picci L et al. Identification of a D579G homozygote cystic fibrosis patient with pancreatic sufficiency and minor lung involvement. Hum Mutat. 1999; 13(2):173. Schrijver I et al. Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum. J Mol Diagn. 2005; 7(2):289-99. Sosnay P et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7.

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

Last Updated: Nov 27, 2021

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