Submissions for variant NM_000492.4(CFTR):c.1712T>C (p.Leu571Ser)

dbSNP: rs397508280

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577164	SCV001360491	likely pathogenic	Cystic fibrosis	2019-01-21	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1712T>C (p.Leu571Ser) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245736 control chromosomes (gnomAD and publication). c.1712T>C has been reported in the literature in a homozygous and at least two compound heterozygote individuals affected with Cystic Fibrosis (Onay 1998, Varon 1995, Lucarelli 2015, Lucarelli 2017). These data indicate that the variant may be associated with disease. In addition, variants located nearby this variant, Y569H, Y569D, Y569C, D572N and P574H, have been reported in HGMD associated with cystic fibrosis, thus suggesting this region is important for CFTR protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577164	SCV002573817	likely pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3_STR, PP3, PP4
Ambry Genetics	RCV000577164	SCV002713548	pathogenic	Cystic fibrosis	2016-08-09	criteria provided, single submitter	clinical testing	The p.L571S pathogenic mutation (also known as c.1712T>C), located in coding exon 13 of the CFTR gene, results from a T to C substitution at nucleotide position 1712. The leucine at codon 571 is replaced by serine, an amino acid with dissimilar properties. This alteration was seen in a patient with cystic fibrosis (CF) who was reported to have p.R347P in the second allele (Varon R et al. Hum. Mutat., 1995;6:219-25). This alteration was also described as homozygous in another CF patient (Onay T et al. Hum. Genet., 1998 Feb;102:224-30). In addition, this alteration has been detected in a few CF cohorts (Angelicheva D et al. Hum. Genet., 1997 Apr;99:513-20; Casals T et al. Hum. Genet., 1997 Dec;101:365-70; Alonso MJ et al. Ann. Hum. Genet., 2007 Mar;71:194-201). Bases on the available evidence, p.L571S is classified as a pathogenic mutation.
Invitae	RCV000577164	SCV003440216	uncertain significance	Cystic fibrosis	2022-04-09	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 571 of the CFTR protein (p.Leu571Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis, pancreatic insufficiency, or pulmonary complications (PMID: 8535440, 9099843, 9439669, 9521595, 17331079). ClinVar contains an entry for this variant (Variation ID: 53356). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577164	SCV000679122	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV001835655	SCV002080658	likely pathogenic	CFTR-related disorder	2020-05-09	no assertion criteria provided	clinical testing