ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3454G>C (p.Asp1152His) (rs75541969)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV000660854 SCV000783093 drug response ivacaftor response - Efficacy 2018-03-23 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
Invitae RCV000046895 SCV000074908 pathogenic Cystic fibrosis 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 1152 of the CFTR protein (p.Asp1152His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs75541969, ExAC 0.05%). This variant has been reported in many individuals affected with congenital absence of the vas deferens (PMID: 21520337, 19843100, 7739684, 22156145, 25304080), chronic pancreatitis (PMID: 23951356, 20460946, 17003641, 15987793), atypical cystic fibrosis (PMID: 18301294, 11883825, 15858154, 23082198, 17594398, 16429425), and bronchiectasis (PMID: 19843100), but rarely in individuals with classic cystic fibrosis (PMID: 18301294). ClinVar contains an entry for this variant (Variation ID: 35867). Experimental studies have shown that this missense change does not affect protein stability or maturation, but does reduce the function of CFTR in cell culture (PMID: 23891399, 25033378, 9804160). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000325638 SCV000227775 pathogenic not provided 2017-05-22 criteria provided, single submitter clinical testing
GeneDx RCV000325638 SCV000329250 pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing The D1152H pathogenic variant has been reported previously is association with cystic fibrosis and congenital bilateral absence of the vas deferens (Chillon et al., 1995; Burgel et al., 2010; Terlizzi et al., 2015). A retrospective case review revealed that the patients homozygous and compound heterozygous for the D1152H variant exhibited very mild clinical expression (Terlizzi et al., 2015). The D1152H variant is observed in 29/10,142 (0.3%) alleles from individuals of Ashkenazi Jewish background in large population cohorts, and no individuals were reported to be homozygous (Lek et al., 2016). The D1152H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In vitro functional studies indicated that the D1152H variant results in a protein whose chloride transport is approximately 57% that of wild-type (VanGoor et al., 2014; LaRusch et al., 2014). We interpret D1152H as a pathogenic variant.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000325638 SCV000511351 pathogenic not provided 2016-10-28 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000046895 SCV000584083 pathogenic Cystic fibrosis 2017-07-05 criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000325638 SCV000601100 likely pathogenic not provided 2019-02-05 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999986 SCV000603066 pathogenic not specified 2018-07-12 criteria provided, single submitter clinical testing The CFTR c.3454G>C; p.Asp1152His variant (rs75541969) is reported in the literature in multiple individuals affected with classic cystic fibrosis or CFTR-related disorders (Chillon 1995, Gallati 2009, Highsmith 2005, LaRusch 2014, Masson 2013, Steiner 2011, Sosnay 2013, CFTR2 database). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 35867), and is found in the general population with an overall allele frequency of 0.038% (104/276606 alleles) in the Genome Aggregation Database. The aspartic acid at codon 1152 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional characterization of the variant protein indicates a significant reduction in chloride and bicarbonate transport activity (LaRusch 2014, Sosnay 2013, Van Goor 2014, Vankeerberghen 1998). Genotype-phenotype correlation studies have demonstrated that this variant, in combination with another pathogenic CFTR variant (e.g. p.Phe508del), is associated with highly variable clinical presentations, ranging from asymptomatic to pancreatic insufficient CF (Burgel 2010, Mussaffi 2006, Terlizzi 2015, CFTR2 database). Based on available information, the p.Asp1152His variant is classified as pathogenic with variable presentation of clinical phenotypes. References: CFTR2 database: http://cftr2.org/ Burgel P et al. Non-classic cystic fibrosis associated with D1152H CFTR mutation. Clin Genet. 2010; 77(4):355-64. Chillon M et al. Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N Engl J Med. 1995; 332(22):1475-80. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009; 19(5):685-94. Highsmith WE Jr et al. A CFTR mutation (D1152H) in a family with mild lung disease and normal sweat chlorides. Clin Genet. 2005; 68(1):88-90. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014; 10(7):e1004376. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013; 8(8):e73522. Mussaffi H et al. Cystic fibrosis mutations with widely variable phenotype: the D1152H example. Pediatr Pulmonol. 2006; 41(3):250-4. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011; 32(8):912-20. Terlizzi V et al. Clinical expression of patients with the D1152H CFTR mutation. J Cyst Fibros. 2015; 14(4):447-52. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998; 7(11):1761-9.
Mendelics RCV000046895 SCV000886266 pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000046895 SCV000916188 pathogenic Cystic fibrosis 2018-08-22 criteria provided, single submitter clinical testing The CFTR c.3454G>C (p.Asp1152His) missense variant has been described in 12 studies in patients with CFTR-related disorders, including in at least 22 in a homozygous state and 179 in a compound heterozygous state (Chillon et al. 1995; Dayangac et al. 2004; Highsmith et al. 2005; Mussaffi et al. 2006; Augarten et al. 2008; Burgel et al. 2010; Peleg et al. 2011; Steiner et al. 2011; Tomaiuolo et al. 2011; Sosnay et al. 2013; LaRusch et al. 2014; Terlizzi et al. 2015). The p.Asp1152His variant, when in combination with another variant known to cause CFTR-related disorders, is associated with an extremely variable phenotype ranging from asymptomatic to cystic fibrosis. The variant is often associated with mild clinical expression, mild pulmonary disease and pancreatic sufficiency (Augarten et al. 2008; Burgel et al. 2010; La Rush et al. 2014). The p.Asp1152His variant was found in a heterozygous state in one of 2957 controls and is reported at a frequency of 0.002859 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies on the p.Asp1152His variant showed chloride transport activity is 57.4% of the wild type (Van Goor et al. 2014). La Rusch et al. (2014) report that the p.Asp1152His variant causes a narrowing of the channel diameter which would affect conductance properties. The p.Asp1152His variant was shown to exhibit normal chloride function in HEK293 cells with significantly reduced bicarbonate permeability and conductance (LaRusch et al. 2014). Vankeerberghen et al. (1998) demonstrated in Xenopus oocytes that the p.Asp1152His variant did not alter the permeability sequence of the CFTR channels but led to whole cell cAMP activated chloride currents that were significantly reduced compared to wild type indicating that the variant interfere with the proper gating of the chloride channels. Based on the collective evidence, the p.Asp1152His variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Johns Hopkins Genomics,Johns Hopkins University RCV000046895 SCV000996035 pathogenic Cystic fibrosis 2019-07-09 criteria provided, single submitter clinical testing
Baylor Genetics RCV001004498 SCV001163543 pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009365 SCV001169218 pathogenic Cystic fibrosis; CFTR-related disorders 2018-01-29 criteria provided, single submitter curation when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD
Ambry Genetics RCV001020342 SCV001181807 pathogenic Inborn genetic diseases 2018-12-18 criteria provided, single submitter clinical testing 2 of classification of c (below) met (2c = 1b);Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
Myriad Women's Health, Inc. RCV000046895 SCV001193906 pathogenic Cystic fibrosis 2019-11-11 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.3454G>C(D1152H) is classified as pathogenic in the context of cystic fibrosis and is associated with a broad spectrum of disease, ranging from clinically asyptomatic to classic cystic fibrosis. Sources cited for classification include the following: PMID 9804160, 19843100, 18301294, 22156145 and 23974870. Classification of NM_000492.3(CFTR):c.3454G>C(D1152H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Integrated Genetics/Laboratory Corporation of America RCV000046895 SCV000052174 pathogenic Cystic fibrosis 2015-07-16 no assertion criteria provided clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000046895 SCV000536841 pathogenic Cystic fibrosis 2015-11-13 no assertion criteria provided research

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