Submissions for variant NM_000492.4(CFTR):c.1043T>A (p.Met348Lys)

gnomAD frequency: 0.00007  dbSNP: rs142920240

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000046210	SCV000074223	benign	Cystic fibrosis	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000339107	SCV000345968	uncertain significance	not provided	2016-09-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000046210	SCV000796944	uncertain significance	Cystic fibrosis	2018-01-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000339107	SCV000883600	likely benign	not provided	2020-03-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000046210	SCV000886368	benign	Cystic fibrosis	2023-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781246	SCV000919154	likely benign	not specified	2021-05-18	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1043T>A (p.Met348Lys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 0.00014 in 251178 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00014 vs 0.013), allowing no conclusion about variant significance. c.1043T>A has been reported in the literature in individuals affected with Cystic Fibrosis (CF) (example: DApice_2004, Liechti-Gallati_1999). However, it has also been found in a healthy homozygous individual (Molinario_2013) and in a patient who presented with respiratory distress, necrotizing enterocolitis and hyperbilirubinemia but a negative sweat test (Hentschel_2012), indicating the variant was not causative for CF. In another family the variant was shown not to co-segregate with the disease (D'Apice_2004). Additionally, the variant has also been found in cis with another pathogenic variant in a CBAVD (Congenital Bilateral Absence of Vas Deferens) and a CF patient with pancreatic insufficiency (Lucarelli_2015). Electrophysiological assessment of CFTR in native rectal epithelium of the patient homozygous for this variant demonstrated normal Cl- secretion (Hentschel_2012). Eight ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=5) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV000046210	SCV001169897	likely benign	Cystic fibrosis	2019-04-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Johns Hopkins Genomics, Johns Hopkins University	RCV000046210	SCV001425327	likely benign	Cystic fibrosis	2020-05-07	criteria provided, single submitter	clinical testing
Pars Genome Lab	RCV000046210	SCV001652835	uncertain significance	Cystic fibrosis	2021-05-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000046210	SCV001822032	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000339107	SCV004700881	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	CFTR: PM1, PP3, BP2, BS3:Supporting, BS4
PreventionGenetics, part of Exact Sciences	RCV004537222	SCV004726169	likely benign	CFTR-related disorder	2019-07-02	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV000046210	SCV001453956	likely benign	Cystic fibrosis	2019-08-06	no assertion criteria provided	clinical testing