NM_000492.4(CFTR):c.4056G>T (p.Gln1352His) AND not specified

Clinical significance:Uncertain significance (Last evaluated: Nov 3, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000029537.2

Allele description [Variation Report for NM_000492.4(CFTR):c.4056G>T (p.Gln1352His)]

NM_000492.4(CFTR):c.4056G>T (p.Gln1352His)

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.4056G>T (p.Gln1352His)
HGVS:
  • NC_000007.14:g.117664780G>T
  • NG_016465.4:g.203997G>T
  • NM_000492.3:c.4056G>T
  • NM_000492.4:c.4056G>TMANE SELECT
  • NP_000483.3:p.Gln1352His
  • NP_000483.3:p.Gln1352His
  • LRG_663t1:c.4056G>T
  • LRG_663:g.203997G>T
  • LRG_663p1:p.Gln1352His
  • NC_000007.13:g.117304834G>T
Protein change:
Q1352H
Links:
dbSNP: rs113857788
NCBI 1000 Genomes Browser:
rs113857788
Molecular consequence:
  • NM_000492.3:c.4056G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000492.4:c.4056G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Summary from all submissions

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

Citations

PubMed

Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens.

Dörk T, Dworniczak B, Aulehla-Scholz C, Wieczorek D, Böhm I, Mayerova A, Seydewitz HH, Nieschlag E, Meschede D, Horst J, Pander HJ, Sperling H, Ratjen F, Passarge E, Schmidtke J, Stuhrmann M.

Hum Genet. 1997 Sep;100(3-4):365-77.

PubMed [citation]
PMID:
9272157

Molecular pathology of the CFTR locus in male infertility.

Claustres M.

Reprod Biomed Online. 2005 Jan;10(1):14-41. Review.

PubMed [citation]
PMID:
15705292
See all PubMed Citations (38)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052189.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (38)

Description

Variant summary: CFTR c.4056G>T (p.Gln1352His) results in a non-conservative amino acid change located in the ABC transporter-like domain of 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 6e-05 in 251226 control chromosomes, predominantly at a frequency of 0.00046 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00046 vs 0.013), allowing no conclusion about variant significance. Another variant at this position, c.4056G>C (legacy c.4188 G>C), which encodes the same p.Gln1352His amino acid change, has been reported in the literature. The Gln1352His variants (in many cases without specifying nucleotide substitution) have been reported in individuals affected with multiple CFTR-Related Diseases, including chronic pancreatitis (e.g. Fujiki_2004, Lee_2003, Lee_2005, Keiles_2006, Nakano_2015, Cho_2016), Congenital Bilateral Absence of the Vas Deferens (CBAVD; e.g. Braekeleer_1996, Dork_1997, Danziger_2004, Ratbi_2007, Steiner_2011, Claustres_2017), and bronchiecstasis (e.g. Lee_2003). In at least several of these patients, a second pathogenic mutation in CFTR was identified, while in others, a second variant was not found. These reports do not contain co-segregation information definitively associating the variant with disease, however several case-control studies report a significant over-representation of the Gln1352His variant in individuals affected with chronic pancreatitis phenotypes (e.g. Lee_2003, Fujuiki_2004, Nakano_2015). The variant has also been reported in healthy controls, including in the compound heterozygous state with known pathogenic alleles in at least three apparently asymptomatic individuals (e.g. Bienvenu_2005, Claustres_2017). The variant has also been reported in individuals affected by severe asthma (e.g. Ngiam_2006), primary sclerosing cholangitis (e.g. Pall_2007), sarcoidosis (e.g. Makrythanasis_2010), and azoospermia (e.g. Ooi_2014). The variant did not segregate with disease in a family with cystic fibrosis (CF), in which the proband carried Gln1352His, Phe508Del, and Tyr122X variants, as two healthy, unaffected family members with the p. Gln1352His variant also carried pathogenic p.Tyr122X in a compound heterozygous state (Bienvenu_2005). At least one publication reports experimental evidence evaluating an impact on protein function, indicating that variant results in defective protein expression and channel kinetics (e.g. Lee_2003). Collectively, the currently available information suggests that the Gln1352His variants could be associated with mild CFTR-related phenotypes, however further evidence such as co-segregation studies are needed to conclusively establish association with these CFTR-related diseases. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance (n=1) and pathogenic/ likely pathogenic (n=2). 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

Last Updated: Nov 10, 2021

Support Center