Submissions for variant NM_000492.4(CFTR):c.842T>C (p.Met281Thr)

gnomAD frequency: 0.00006  dbSNP: rs397508802

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281739	SCV000697047	uncertain significance	not specified	2024-06-06	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.842T>C (p.Met281Thr) 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 8e-06 in 249438 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.842T>C has been reported in the literature as a non-informative genotype (second allele not specified) in a pancreatically sufficient individual with intermediate sweat chloride levels who presented with chronic pancreatitis (example, Casals_2004 cited in deCid_2010). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15097853, 26471113, 19812525). ClinVar contains an entry for this variant (Variation ID: 54067). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000577667	SCV000793019	uncertain significance	Cystic fibrosis	2017-07-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000577667	SCV002027371	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000577667	SCV002677804	uncertain significance	Cystic fibrosis	2022-10-11	criteria provided, single submitter	clinical testing	The p.M281T variant (also known as c.842T>C and c.974T>C) is located in coding exon 7 of the CFTR gene. This variant results from a T to C substitution at nucleotide position 842. The methionine at codon 281 is replaced by threonine, an amino acid with similar properties. This variant was described in an individual with pancreatitis, sweat chloride levels of 62 mmol/L, pancreatic sufficiency, and normal respiratory function; another pathogenic variant was not described (Casals et al. Pancreas 2004 May;28(4):374-9). 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.
Fulgent Genetics, Fulgent Genetics	RCV002483058	SCV002790705	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2022-01-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577667	SCV003290582	uncertain significance	Cystic fibrosis	2022-07-04	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 281 of the CFTR protein (p.Met281Thr). This variant is present in population databases (rs397508802, gnomAD 0.004%). This missense change has been observed in individual(s) with chronic pancreatitis (PMID: 15097853). ClinVar contains an entry for this variant (Variation ID: 54067). 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: "Benign"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577667	SCV000679175	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV001831804	SCV002078145	uncertain significance	CFTR-related disorder	2018-05-11	no assertion criteria provided	clinical testing