Submissions for variant NM_000492.4(CFTR):c.1322T>C (p.Leu441Pro)

dbSNP: rs397508188

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577476	SCV003800780	pathogenic	Cystic fibrosis	2023-01-30	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1322T>C (p.Leu441Pro) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (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 4.1e-06 in 241482 control chromosomes (gnomAD). c.1322T>C has been reported in the literature in multiple individuals affected with Cystic Fibrosis, primarily of Korean ancestry (e.g. Gee_2010, Schrijver_2016, Kim_2022). These data indicate that the variant is likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (e.g. Gee_2010, Shishido_2020, Kim_2022). These results showed that the variant results in a decreased efficiency in protein folding and that the protein is found almost exclusively in the ER core-glycosylated immature form, indicating a defect in the ER-to-Golgi trafficking of the secretory pathway of membrane protein. Indeed, while the WT CFTR protein is located on the plasma membrane, immunostaining showed the L441P mutant is localized to the ER, and cAMP treatment failed to activate the Cl- currents in cells transfected with the mutant protein (Gee_2010). 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 pathogenic.
Ambry Genetics	RCV000577476	SCV004093409	uncertain significance	Cystic fibrosis	2023-06-16	criteria provided, single submitter	clinical testing	The p.L441P variant (also known as c.1322T>C), located in coding exon 10 of the CFTR gene, results from a T to C substitution at nucleotide position 1322. The leucine at codon 441 is replaced by proline, an amino acid with similar properties. This alteration has been identified with a second CFTR alteration in multiple individuals diagnosed with cystic fibrosis however phase was not determined (Kim HY et al. Allergy Asthma Immunol Res, 2022 Sep;14:494-504). In functional studies, this variant was shown to decrease CFTR maturation/processing and failed to activate the chloride currents compared to the wild-type CFTR (Gee HY et al. J Korean Med Sci, 2010 Jan;25:166-71; Kim HY et al. Allergy Asthma Immunol Res, 2022 Sep;14:494-504). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577476	SCV000678888	not provided	Cystic fibrosis		no assertion provided	literature only