Submissions for variant NM_000492.4(CFTR):c.3612G>A (p.Trp1204Ter)

gnomAD frequency: 0.00001  dbSNP: rs121908765

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000056384	SCV000087511	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
Eurofins Ntd Llc (ga)	RCV000790735	SCV000227899	pathogenic	not provided	2013-01-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000056384	SCV000485430	pathogenic	Cystic fibrosis	2015-12-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781267	SCV000919179	pathogenic	not specified	2018-05-04	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3612G>A (p.Trp1204X) 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. The variant was observed with an allele frequency of 1.2e-05 in 245006 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (1.2e-05 vs 0.013), allowing no conclusion about variant significance. The variant, c.3612G>A, has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Sosnay_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submssions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000056384	SCV001167218	pathogenic	Cystic fibrosis	2019-07-03	criteria provided, single submitter	clinical testing	Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information.
CFTR-France	RCV001009526	SCV001169621	pathogenic	Cystic fibrosis; CFTR-related disorder	2018-01-29	criteria provided, single submitter	curation	the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both
Labcorp Genetics (formerly Invitae), Labcorp	RCV000056384	SCV001592633	pathogenic	Cystic fibrosis	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1204*) 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 present in population databases (rs121908765, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 7522211, 23974870). ClinVar contains an entry for this variant (Variation ID: 53779). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000790735	SCV002525783	pathogenic	not provided	2021-12-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000056384	SCV002616485	pathogenic	Cystic fibrosis	2022-03-07	criteria provided, single submitter	clinical testing	The p.W1204* pathogenic mutation (also known as c.3612G>A and 3744G>A), located in coding exon 22 of the CFTR gene, results from a G to A substitution at nucleotide position 3612. This changes the amino acid from a tryptophan to a stop codon within exon 22. The c.3612G>A mutation was identified in an individual who presented with classic cystic fibrosis (CF) symptoms (Schrijver I et al. J Mol Diagn. 2005;7(2):289-299). The p.W1204* pathogenic mutation was described in a one individual with CF confirmed in trans with p.F508del (Ghanem N, Genomics 1994 May; 21(2):434-6). In a study of California Hispanic and African American individuals with CF and at least one unidentified mutant allele, this mutation was identified on five CF chromosomes (Alper OM, Hum. Mutat. 2004 Oct; 24(4):353). This pathogenic mutation is associated with elevated sweat chloride levels, decreased lung function, pancreatic insufficiency, and Pseudomonas infection (Sosnay PR, Nat. Genet. 2013 Oct; 45(10):1160-7; The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed March 7, 2022). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV003474585	SCV004213418	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-08-27	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826668	SCV002075856	pathogenic	CFTR-related disorder	2017-03-17	no assertion criteria provided	clinical testing