ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1721C>A (p.Pro574His) (rs121908758)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CFTR2 RCV000007539 SCV000924269 pathogenic Cystic fibrosis 2017-12-08 reviewed by expert panel research
Baylor Genetics RCV001004269 SCV001163145 likely pathogenic Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation criteria provided, single submitter clinical testing
CFTR-France RCV001009367 SCV001169220 pathogenic Cystic fibrosis; CFTR-related disorders 2018-03-09 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
Myriad Women's Health, Inc. RCV000007539 SCV001194016 likely pathogenic Cystic fibrosis 2019-12-16 criteria provided, single submitter clinical testing NM_000492.3(CFTR):c.1721C>A(P574H) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 16132229, 20059485, 12815607, 10362539, 7534226, 10923036 and 754013. Classification of NM_000492.3(CFTR):c.1721C>A(P574H) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses and is very rare or not present in genetic databases of healthy individuals. Please note: this variant was assessed in the context of healthy population screening.
Invitae RCV000007539 SCV001583409 pathogenic Cystic fibrosis 2020-07-20 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 574 of the CFTR protein (p.Pro574His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with cystic fibrosis and congenital bilateral absence of vas deferens (PMID: 10923036, 9239681, 2236053). ClinVar contains an entry for this variant (Variation ID: 7119). This variant has been reported to affect CFTR protein function (PMID: 21594800, 29805046 ). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000007539 SCV001737734 pathogenic Cystic fibrosis 2021-06-11 criteria provided, single submitter clinical testing Variant summary: CFTR c.1721C>A (p.Pro574His) results in a non-conservative amino acid change located in the ABC transporter-like (IPR003439) 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 8e-06 in 250350 control chromosomes. c.1721C>A has been reported in compound heterozygosity with another pathogenic variant in multiple individuals affected with Cystic Fibrosis in the literature (e.g. Kerem_1990, McCague_2019, Dadgostar_2021). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (e.g. Champigny_1995, Cai_2011, Raraigh_2018, Han_2018). The most pronounced variant effect results in <10% of normal CFTR activity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000007539 SCV000027740 pathogenic Cystic fibrosis 1990-11-01 no assertion criteria provided literature only

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