Submissions for variant NM_000492.4(CFTR):c.3763T>C (p.Ser1255Pro)

dbSNP: rs121909041

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000007613	SCV000245924	pathogenic	Cystic fibrosis	2017-03-17	reviewed by expert panel	research
PharmGKB	RCV001787320	SCV000268178	drug response	ivacaftor response - Efficacy	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
Counsyl	RCV000007613	SCV000486849	likely pathogenic	Cystic fibrosis	2016-08-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000007613	SCV000696989	pathogenic	Cystic fibrosis	2017-07-10	criteria provided, single submitter	clinical testing	Variant summary: The CFTR variant, c.3763T>C (p.Ser1255Pro) involves a conserved nucleotide located in the nucleotide-binding domain 2 that 4/4 in silico tools predict damaging outcome. This variant is absent in 121154 ExAC chromosomes. This variant was first found in a Belgian CF patient who was compound heterozygous for this variant and p.Phe508del (Lissens_1992). It has also been reported in another two CF patients without detailed genotype information (Claustres_2000, Schrijver_2016). Currently, it has been reported in 10 CF patients in CFTR2 database. Functional studies have shown that S1255P is defective in channel gating as well as chloride transport (Anderson_1992, Choi_2001, Yu_2012). These defects were shown to be compensated by ivacaftor treatment (Yu_2012). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics	RCV002247264	SCV002518690	pathogenic	Hereditary pancreatitis	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000007613	SCV002623381	pathogenic	Cystic fibrosis	2024-10-16	criteria provided, single submitter	clinical testing	The p.S1255P pathogenic mutation (also known as c.3763T>C), located in coding exon 23 of the CFTR gene, results from a T to C substitution at nucleotide position 3763. The serine at codon 1255 is replaced by proline, an amino acid with similar properties. This alteration is considered a class III mutation, meaning it produces a full-length CFTR protein which incorporates normally into the cell membrane, but has defective gating and blocks the flow of chloride ions through the CFTR channel (De Boeck K et al. J. Cyst. Fibros., 2014 Jul;13:403-9). This mutation was identified in a individual diagnosed with cystic fibrosis confirmed with sweat chloride levels in trans with p.F508del (Lissens W et al. Hum. Mol. Genet., 1992 Sep;1:441-2). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007613	SCV003440108	pathogenic	Cystic fibrosis	2022-07-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CFTR function (PMID: 11242048). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1255 of the CFTR protein (p.Ser1255Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 1284530, 30548586). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7192). 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 tolerated.
OMIM	RCV000007613	SCV000027814	pathogenic	Cystic fibrosis	1993-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000007613	SCV001454283	pathogenic	Cystic fibrosis	2020-09-16	no assertion criteria provided	clinical testing