Submissions for variant NM_000492.4(CFTR):c.3294G>T (p.Trp1098Cys)

dbSNP: rs397508533

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000757800	SCV000924220	pathogenic	Cystic fibrosis	2018-08-31	reviewed by expert panel	research
Mendelics	RCV000757800	SCV000886176	likely pathogenic	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004306	SCV001163183	likely pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000757800	SCV002265909	likely pathogenic	Cystic fibrosis	2021-11-24	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 618905). This variant is also known as c.3426G>T. This missense change has been observed in individual(s) with cystic fibrosis (PMID: 10798368, 14998948, 16963320, 21416780). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 1098 of the CFTR protein (p.Trp1098Cys). Experimental studies have shown that this missense change affects CFTR function (PMID: 30046002). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Trp1098 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7537150, 8662892). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000757800	SCV003934568	likely pathogenic	Cystic fibrosis	2023-05-01	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.3294G>T (p.Trp1098Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. The variant was absent in 251088 control chromosomes (gnomAD). c.3294G>T has been reported in the literature in individuals affected with Cystic Fibrosis and Congenital Bilateral Absence Of The Vas Deferens (examples: Orozco_2000, Danziger_2004). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Han_2018). Other variants affecting the same amino acid residue is reported as associated with Cystic Fibrosis in HGMD and has been classified pathogenic in ClinVar (ID 53707). The following publications have been ascertained in the context of this evaluation (PMID: 10798368, 14998948, 21416780, 30046002). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.