Submissions for variant NM_000492.4(CFTR):c.531del (p.Ile177fs)

dbSNP: rs121908771

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056393	SCV000071489	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Baylor Genetics	RCV001004434	SCV001163479	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000056393	SCV001193915	pathogenic	Cystic fibrosis	2019-12-07	criteria provided, single submitter	clinical testing	NM_000492.3(CFTR):c.531delT(I177Mfs*12, aka 663delT) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.531delT(I177Mfs*12, aka 663delT) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056393	SCV001588427	pathogenic	Cystic fibrosis	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile177Metfs*12) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 10993719, 15365999, 23974870). This variant is also known as 663delT. ClinVar contains an entry for this variant (Variation ID: 53991). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000056393	SCV002041565	pathogenic	Cystic fibrosis	2021-11-08	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.531delT (p.Ile177MetfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250720 control chromosomes. c.531delT has been reported in the literature in multiple individuals affected with Cystic Fibrosis (example Sosnay_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories and an expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000056393	SCV002640725	pathogenic	Cystic fibrosis	2016-06-29	criteria provided, single submitter	clinical testing	The c.531delT pathogenic mutation, located in coding exon 5 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 531, causing a translational frameshift with a predicted alternate stop codon (p.I177Mfs*12). This mutation was first identified in a Hispanic individual with cystic fibrosis in conjunction with another frameshift alteration; this individual was pancreatic insufficient, had meconium ileus, and elevated sweat chloride levels (Wang J, et al. Mol. Genet. Metab. 2000 Aug; 70(4):316-21). This mutation is associated with elevated sweat chloride levels, lung disease, and pancreatic insufficiency (Sosnay PR, et al. Nat Genet. 2013; 45(10):1160-7, Supplementary Table). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003114234	SCV003799526	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing	The CFTR c.531del; p.Ile177MetfsTer12 variant (rs121908771), also known as 663delT, is reported in cystic fibrosis patients and often associated with pancreatic insufficiency (Sosnay 2013, Wang 2000, CFTR2 database). This variant is also reported in ClinVar (Variation ID: 53991). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org/ 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. Wang J et al. A novel CFTR frame-shift mutation, 935delA, in two Hispanic cystic fibrosis patients. Mol Genet Metab. 2000; 70(4):316-21. PMID: 10993719.
Baylor Genetics	RCV003474608	SCV004213363	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826692	SCV002080158	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing