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

gnomAD frequency: 0.00033  dbSNP: rs75541969

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV000660854	SCV000783093	drug response	ivacaftor response - Efficacy	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Invitae	RCV000046895	SCV000074908	pathogenic	Cystic fibrosis	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1152 of the CFTR protein (p.Asp1152His). This variant is present in population databases (rs75541969, gnomAD 0.3%). This missense change has been observed in individuals with congenital absence of the vas deferens and classic cystic fibrosis (PMID: 7739684, 11883825, 15858154, 15987793, 16429425, 17003641, 17594398, 18301294, 19843100, 20460946, 21520337, 22156145, 23082198, 23951356, 25304080). ClinVar contains an entry for this variant (Variation ID: 35867). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 9804160, 23891399, 25033378). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	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	2023-08-03	criteria provided, single submitter	clinical testing	The CFTR c.3454G>C (p.Asp1152His) variant has been reported in the published literature in individuals with cystic fibrosis and may be associated with a milder presentation than typical pathogenic variants in CFTR (PMIDs: 27659740 (2017), 27214204 (2016), 27086061 (2016), 26755536 (2016), 25910067 (2015), 25583415 (2015)). This variant is also reported in individuals with CFTR-related disorders (PMIDs: 7739684 (1995), 22020151 (2012), 23951356 (2013), 27171515 (2016), 27738188 (2017)). In addition, published functional studies demonstrate that this variant partially reduces chloride transport activity, affects proper chloride channel gating, alters bicarbonate conductance, and results in decreased conductance and permeability (PMIDs: 32414100 (2020), 25033378 (2014), 23891399 (2014), 9804160 (1998)). The frequency of this variant in the general population, 0.0026 (27/10360 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000325638	SCV000603066	pathogenic	not provided	2023-10-24	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 also reported in ClinVar (Variation ID: 35867), and is found in the general population with an overall allele frequency of 0.038% (106/282326 alleles) in the Genome Aggregation Database. The aspartic acid at codon 1152 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.657). 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 varying clinical consequences. References: Link to 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. PMID: 19843100. 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. PMID: 7739684. 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. PMID: 20021716. 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. PMID: 15952991. 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. PMID: 25033378. 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. PMID: 23951356. Mussaffi H et al. Cystic fibrosis mutations with widely variable phenotype: the D1152H example. Pediatr Pulmonol. 2006; 41(3):250-4. PMID: 16429425. 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. PMID: 23974870. 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. PMID: 21520337. Terlizzi V et al. Clinical expression of patients with the D1152H CFTR mutation. J Cyst Fibros. 2015; 14(4):447-52. PMID: 25583415. 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. PMID: 23891399. 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. PMID: 9736778.
Mendelics	RCV000046895	SCV000886266	pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 disorder	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	RCV000046895	SCV001181807	pathogenic	Cystic fibrosis	2022-01-13	criteria provided, single submitter	clinical testing	The p.D1152H pathogenic mutation (also known as c.3454G>C), located in coding exon 21 of the CFTR gene, results from a G to C substitution at nucleotide position 3454. The aspartic acid at codon 1152 is replaced by histidine, an amino acid with similar properties. In one study, 45 individuals with a p.D1152H allele in trans with another CFTR mutation were identified with features including bronchiectasis and congenital bilateral absence of the vas deferens (CBAVD) (Burgel PR et al. Clin. Genet., 2010 Apr;77:355-64). Numerous studies have concluded this mutation is often associated with a mild cystic fibrosis presentation or CFTR-related disorder characterized by mild pulmonary disease, varying clinical expression, and prolonged survival (Schulz A et al. J. Cyst. Fibros., 2016 Sep;15:641-4; Gaitch N et al. Pancreatology Apr;16:515-22; Lucarelli M et al. Mol. Med., 2015 Apr;21:257-75) and it has been described as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; Salinas DB et al. PLoS ONE, 2016 May;11:e0155624). Functional in vitro studies found that cells carrying this pathogenic mutation retained the ability to conduct chloride (Sosnay PR et al. Nat. Genet. 2013 Oct; 45(10):1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000325638	SCV001449991	pathogenic	not provided	2017-10-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001334484	SCV001527341	pathogenic	Congenital bilateral aplasia of vas deferens from CFTR mutation	2018-02-13	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. [PMID 7739684, 26990548, 22020151, 18301294, 19843100, 18456578, 19212293, 22310382, 20021716, 24082139, 25033378, 25033378, 22975760, 11547256, 23951356, 12124706, 27171515, 22156145, 20460946, 17617039, 23974870, 21520337, 25087612, 25583415, 21679131, 23891399]
Genome-Nilou Lab	RCV000046895	SCV001810328	pathogenic	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Institute of Reproductive Genetics, University of Münster	RCV001642237	SCV001860330	pathogenic	Obstructive azoospermia	2022-03-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000325638	SCV002019233	pathogenic	not provided	2021-03-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000046895	SCV002030178	pathogenic	Cystic fibrosis	2021-10-26	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
AiLife Diagnostics, AiLife Diagnostics	RCV000325638	SCV002502719	pathogenic	not provided	2021-08-04	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000046895	SCV002507338	pathogenic	Cystic fibrosis	2021-08-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000325638	SCV002586192	pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CFTR: PM3:Very Strong, PM2:Supporting, PS3:Supporting
PreventionGenetics, part of Exact Sciences	RCV001826514	SCV004111459	likely pathogenic	CFTR-related disorder	2024-01-30	criteria provided, single submitter	clinical testing	The CFTR c.3454G>C variant is predicted to result in the amino acid substitution p.Asp1152His. This variant has been found in 358 patients who also carried a p.Phe508del variant (cftr2.org). These individuals had slightly elevated chloride concentration of 43 mEq/L on a sweat test (normal <40 mEq/L). Individuals less than 20 years of age had normal lung function, but 27% had pancreatic insufficiency (cftr2.org; Sosnay et al. 2013. PubMed ID: 23974870). This variant, when present with a second pathogenic variant, has been reported in patients with variable clinical presentations including bronchiectasis, pancreas insufficiency, chronic cough, and congenital bilateral absence of the vas deferens (Feldmann et al. 2003. PubMed ID: 12955726; Terlizzi et al. 2015. PubMed ID: 25583415). This variant is reported in 0.26% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV000046895	SCV004183529	pathogenic	Cystic fibrosis	2023-10-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473142	SCV004211630	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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
MAGI's Lab - Research, MAGI Group	RCV001283745	SCV001432688	pathogenic	Male infertility		no assertion criteria provided	provider interpretation
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000325638	SCV001808839	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000325638	SCV001953101	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000325638	SCV001963164	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000325638	SCV001973888	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001826514	SCV002075827	pathogenic	CFTR-related disorder	2018-03-21	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001826514	SCV002507422	pathogenic	CFTR-related disorder	2021-08-23	no assertion criteria provided	clinical testing