ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1327G>T (p.Asp443Tyr) (rs147422190)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046274 SCV000074287 pathogenic Cystic fibrosis 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 443 of the CFTR protein (p.Asp443Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs147422190, ExAC 0.05%). This variant has been reported in trans with a pathogenic variant in individuals affected with congenital absence of the vas deferens (CAVD) (PMID: 21520337). Additionally, this variant frequently occurs in cis with the missense variants p.Gly576Ala and p.Arg668Cys. This haplotype has been reported in individuals affected by CFTR-related diseases including CAVD, idiopathic chronic pancreatitis (ICP), chronic sinusitus, and bronchiectasis (PMID: 10922395, 21520337, 22678879, 23951356, 15126740). ClinVar contains an entry for this variant (Variation ID: 53229). Experimental studies have shown that the p.Asp443Tyr missense variant partially impairs the maturation and localization of the CFTR protein. Furthermore, when this variant occurs in combination with p.Gly576Ala and p.Arg668Cys, CFTR chloride channel conductance is decreased (PMID: 22678879). In this summary, this missense variant is a mild loss of function CFTR allele that has been reported in individuals with CFTR-related diseases. It has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150335 SCV000197437 uncertain significance not specified 2014-06-05 criteria provided, single submitter clinical testing The Asp443Tyr variant in CFTR has been reported in >50 compound heterozygous ind ividuals with varying clinical diagnoses, including congenital bilateral absence of the van deferens (CBAVD), diffuse bronchiectasis, idiopathic pancreatitis, a nd cystic fibrosis (de Meeus 1997, El-Seedy 2012); however most of these individ uals carried one or more CFTR variants in cis with this variant. This variant be en identified in 2/8588 European American and 2/4400 African American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs147422190). Functional data suggest that the Asp443Tyr variant may alter CFT R protein maturation (El-Seedy 2012), however this in vivo assay may not accurat ely reflect biological function. Computational prediction tools and evolutionary conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Asp443Tyr variant is uncertain.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078976 SCV000224838 pathogenic not provided 2012-12-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078976 SCV000601041 likely pathogenic not provided 2017-06-09 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000150335 SCV000603073 pathogenic not specified 2019-01-09 criteria provided, single submitter clinical testing
Counsyl RCV000046274 SCV000800743 uncertain significance Cystic fibrosis 2018-04-02 criteria provided, single submitter clinical testing
Mendelics RCV000046274 SCV000886146 likely pathogenic Cystic fibrosis 2018-11-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000046274 SCV000916180 likely pathogenic Cystic fibrosis 2018-09-18 criteria provided, single submitter clinical testing The CFTR c.1327G>T (p.Asp443Tyr) missense variant has been reported in a compound heterozygous state in five individuals with chronic sinusitis and bronchitis and in a heterozygous state in one proband with congenital uni- or bilateral absence of the vas deferens (de Meeus et al. 1997; Mieusset et al. 2016). The p.Asp443Tyr variant has been reported as part of a complex allele, in cis with c.1727G>C (p.Gly576Ala) and c.2002C>T (p.Arg668Cys) in 57 probands in a compound heterozygous state and in three probands in a heterozygous state (El-Seedy et al. 2012; Abou Alaiwa et al. 2014). Abramowicz et al. (2000) reported the p.[Asp443Tyr;Gly576Ala;Arg668Cys] variant in a compound heterozygous state in a fetus with hyperechoic bowel, a sibling with a history of lower respiratory tract infection and slightly raised sweat chloride, and in an asymptomatic sibling. The p.[Asp443Tyr;Gly576Ala;Arg668Cys] complex allele has been reported in four of 1,423 controls. The p.Asp443Tyr variant is reported at a frequency of 0.000461 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies indicate that p.[Asp443Tyr;Gly576Ala;Arg668Cys] alters CFTR maturation and chloride conductance but retains some residual function, which is consistent with mild or moderate phenotypes. Based on the evidence, the p.Asp443Tyr variant is classified as likely pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000046274 SCV000919136 pathogenic Cystic fibrosis 2020-02-25 criteria provided, single submitter clinical testing Variant summary: CFTR c.1327G>T (p.Asp443Tyr) 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 0.00026 in 242986 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Classic or Non-Classic Cystic Fibrosis, allowing no conclusion about variant significance. This variant has also been reported to form a haplotype with two other variants, namely, c.1727G>C (p.Gly576Ala) and c.2002C>T (p.Arg668Cys). This complex haplotype c.[1327G>T;1727G>C;2002C>T] (p.[Asp443Tyr;Gly576Ala;Arg668Cys]), has been reported to be pathogenic for CFTR-RD. When ascertained conservatively for its occurrence in isolation, c.1327G>T alone (without the complex haplotype) has been reported in the literature in a compound heterozygous state with other pathogenic CFTR alleles in multiple individuals affected with features of sweat chloride positive classic Cystic Fibrosis, Non-classic Cystic Fibrosis such as CBAVD and settings of infertility (example, Claustres_2000, Steiner_2011, Viville_2000, Morea_2005). However, non-reporting of the other two variants that would constitute a complex allele in these reports cannot be entirely ruled out. Nevertheless, these data indicate that this variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function in isolation as well as part of the complex haplotype. The most pronounced isolated variant effect reports conflicting findings between studies ranging from no effect (El-Seedy_2012) to intermediate levels (Raraigh_2018) of chloride channel function (approximately 50% of WT levels) and a moderate alteration of CFTR maturation and localization (El-Seedy_2012). In one of these studies, the authors concluded that the combination of p.Gly576Ala and p.Arg668Cys affecting chloride channel activity coupled with p.Asp443Tyr effecting protein maturation would account for the pathogenicity of the overall haplotype (El-Seedy_2012). In contrast however, c.1727G>C and c.2002C>T have been reported as non-CF causing in isolation based on a large study evaluating the functional consequences of CFTR variants (Sosnay_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=2, Likely pathogenic, n=3, and VUS, n=1). Some of these submitters have cited overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant in isolation was classified as pathogenic for CFTR-related disorders.
Baylor Genetics RCV001004444 SCV001163489 likely pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009469 SCV001169564 pathogenic CFTR-related disorders 2018-03-26 criteria provided, single submitter curation
Ambry Genetics RCV001011047 SCV001171326 likely pathogenic Inborn genetic diseases 2019-09-17 criteria provided, single submitter clinical testing 2 of classification of c (below) met (2c = 1b);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other strong data supporting pathogenic classification ;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078976 SCV001250505 pathogenic not provided 2019-02-01 criteria provided, single submitter clinical testing
Johns Hopkins Genomics,Johns Hopkins University RCV000046274 SCV001431520 likely pathogenic Cystic fibrosis 2020-08-20 criteria provided, single submitter clinical testing CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information.

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