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

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 4, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001375489.12

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

NM_000492.4(CFTR):c.4056G>C (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>C (p.Gln1352His)
HGVS:
  • NC_000007.14:g.117664780G>C
  • NG_016465.4:g.203997G>C
  • NM_000492.4:c.4056G>CMANE SELECT
  • NP_000483.3:p.Gln1352His
  • NP_000483.3:p.Gln1352His
  • LRG_663t1:c.4056G>C
  • LRG_663:g.203997G>C
  • LRG_663p1:p.Gln1352His
  • NC_000007.13:g.117304834G>C
  • NM_000492.3:c.4056G>C
Protein change:
Q1352H; GLN1352HIS
Links:
OMIM: 602421.0133; dbSNP: rs113857788
NCBI 1000 Genomes Browser:
rs113857788
Molecular consequence:
  • NM_000492.4:c.4056G>C - 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
SCV000696997Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Uncertain significance
(Dec 4, 2023)
germlineclinical testing

PubMed (25)
[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

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

Genetic evidence for CFTR dysfunction in Japanese: background for chronic pancreatitis.

Fujiki K, Ishiguro H, Ko SB, Mizuno N, Suzuki Y, Takemura T, Yamamoto A, Yoshikawa T, Kitagawa M, Hayakawa T, Sakai Y, Takayama T, Saito M, Kondo T, Naruse S.

J Med Genet. 2004 May;41(5):e55. No abstract available.

PubMed [citation]
PMID:
15121783
PMCID:
PMC1735764
See all PubMed Citations (25)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696997.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (25)

Description

Variant summary: CFTR c.4056G>C (p.Gln1352His) 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 allele was found at a frequency of 0.00066 in 1619220 control chromosomes, predominantly at a frequency of 0.019 within the East Asian subpopulation in the gnomAD database, including 16 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis phenotype (0.013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant was found with even higher allele frequencies in several East Asian subpopulations, e.g. in the Japanese (with an allele frequency of 0.023 from about 14,000 healthy Japanese individuals in the jMorp database [PMID: 33179747]) and in the Vietnamese (with an allele frequency of 0.05 in 406 unrelated healthy Kinh Vietnamese individuals [PMID: 31180159]), suggesting this variant may be a benign polymorphism found primarily in East Asian populations. On the other hand, the c.4056G>C variant is frequently reported in men with CBAVD in conjunction with a second pathogenic variant, especially the 5T allele. However, one study reported the variant in two unaffected siblings who also carried a pathogenic CFTR mutation in trans (p.Y122X), including an apparently fertile male, suggesting the variant may not be fully penetrant or is not pathogenic (Bienvenu_2005). A recent study found the variant in 32/276 Chinese CAVD patients (i.e. with an allele frequency of 5.98%, including 1 homozygote), and in only 1 allele from 50 control individuals (Luo_2021). This variant is also seen with other phenotypes such as CF, pancreatitis, asthma, nontuberculous mycobacterial lung disease, and bronchiectasis, and the risk association score from several independent publications suggest that this variant is possibly associated with these CF-related phenotypes. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-30% of normal activity (Lee_2003). The following publications have been ascertained in the context of this evaluation (PMID: 15463840, 16596947, 17539902, 28603918, 9272157, 15121783, 20021716, 29997923, 17003641, 33663443, 31180159, 12952861, 22483971, 32777524, 25492507, 16678503, 20558957, 29520692, 17329263, 33374015, 31682332, 21520337, 28608624, 19812525, 20233062). Fifteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=3), pathogenic/likely pathogenic (n=3) and VUS (n=9). Based on the evidence outlined above, the variant was classified as VUS.

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

Last Updated: Jul 15, 2024