ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3454G>C (p.Asp1152His) (rs75541969)

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Total submissions: 14
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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 2018-12-27 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 RCV000325638 SCV000603066 pathogenic not provided 2017-06-11 criteria provided, single submitter clinical testing
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
Integrated Genetics/Laboratory Corporation of America RCV000046895 SCV000052174 pathogenic Cystic fibrosis 2015-07-16 no assertion criteria provided clinical testing
Counsyl RCV000046895 SCV000485220 pathogenic Cystic fibrosis 2016-07-18 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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