Submissions for variant NM_000492.4(CFTR):c.2855T>C (p.Met952Thr)

gnomAD frequency: 0.00019  dbSNP: rs142773283

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046702	SCV001981590	uncertain significance	Cystic fibrosis	2019-12-20	reviewed by expert panel	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046702	SCV000074715	likely pathogenic	Cystic fibrosis	2025-01-23	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 952 of the CFTR protein (p.Met952Thr). This variant is present in population databases (rs142773283, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with CFTR related disorder, chronic pancreatitis, congenital bilateral absence of the vas deferens, and/or elevated chlorine and sodium levels (PMID: 10875853, 17003641, 20977904, 25087612, 27026144, 29589582, 34949556). ClinVar contains an entry for this variant (Variation ID: 53579). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect CFTR function (PMID: 34949556). This variant disrupts the p.Met952 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10200050, 15070876, 15287992, 16272798, 16980811, 21520337, 23276700). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046702	SCV000696929	pathogenic	Cystic fibrosis	2024-10-08	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2855T>C (p.Met952Thr) 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 0.00037 in 1613954 control chromosomes in the gnomAD database, including 1 homozygote with an XX sex chromosome complement. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00037 vs 0.013). c.2855T>C has been reported in the literature in mutiple individuals affected with CFTR-Related Diseases, including pancreatitis, congenital absence of the vas deferens, and cystic fibrosis (example, Mak_1999, Casals_2000, Medza_2021, Stahl_2019, Keiles_2006, Schneider_2011). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.2856G>A, p.Met952Ile), supporting the critical relevance of codon 952 to CFTR protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 21.27% of normal chloride channel conductance relative to wild type (example, Bihler_2024) however other laboratories have observed different results in other cell lines (example, Hatton_2022). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 27026144, 10875853, 14551163, 29589582, 34949556, 17003641, 25033378, 10376575, 26354092, 24451227, 33919435, 32773111, 11796591, 24697796, 25735457, 34782259, 31310009, 34996830, 20977904, 31682332, 30420236, 33322690, 16840743, No_PMID). ClinVar contains an entry for this variant (Variation ID: 53579). Based on the evidence outlined above, the variant was classified as pathogenic.
Eurofins Ntd Llc (ga)	RCV000587345	SCV000702493	uncertain significance	not provided	2016-10-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624171	SCV000742086	uncertain significance	Inborn genetic diseases	2014-06-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV005229868	SCV000883592	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2023-12-04	criteria provided, single submitter	clinical testing	The CFTR c.2855T>C; p.Met952Thr variant (rs142773283) is reported in the literature in multiple individuals affected with CFTR-related disorders when found with a pathogenic variant on the opposite chromosome (Cabrol 2016, Casals 2000, Gilljam 2004, Mak 1999, Wilschanski 2006). This variant is listed in ClinVar (Variation ID: 53579), and is observed in the general population with an overall allele frequency of 0.025% (71/282774 alleles, including a single homozygote) in the Genome Aggregation Database. The methionine at codon 952 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.924). Additionally, another variant at this codon (c.2856G>C; p.Met952Ile) has been reported in individuals with CFTR-related disorders (Steiner 2011, Uzun 2005). While the p.Met952Thr variant is unlikely to cause classic cystic fibrosis, it is considered likely pathogenic for CFTR-related disorders. References: Cabrol C et al. Aquagenic Palmoplantar Keratoderma as a CFTR-related Disorder. Acta Derm Venereol. 2016 Aug 23;96(6):848-9. PMID: 27026144. Casals T et al. Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum Reprod. 2000; 15(7):1476-83. PMID: 10875853. Gilljam M et al. Airway inflammation and infection in congenital bilateral absence of the vas deferens. Am J Respir Crit Care Med. 2004; 169(2):174-9. PMID: 14551163. Mak V et al. Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA. 1999; 281(23):2217-24. PMID: 10376575. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011; 32(8):912-20. PMID: 21520337. Uzun S et al. Cystic fibrosis transmembrane conductance regulator gene mutations in infertile males with congenital bilateral absence of the vas deferens. Tohoku J Exp Med. 2005 Dec;207(4):279-85. PMID: 16272798. Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006; 174(7):787-94. PMID: 16840743.
Illumina Laboratory Services, Illumina	RCV000046702	SCV000916182	likely pathogenic	Cystic fibrosis	2018-12-11	criteria provided, single submitter	clinical testing	The CFTR c.2855T>C (p.Met952Thr) missense variant has been reported in at least six studies and is reported in at least six individuals with CFTR-related disorders. Three of the individuals were males presenting with congenital bilateral absence of the vas deferens (CBAVD) in whom the p.Met952Thr variant was identified in a compound heterozygous state with the p.Phe508del variant (Mak et al. 1999; Casals et al. 2000; Wilschanski et al. 2006). In addition one individual with aquagenic palmoplantar keratoderma also carried the variant in a compound heterozygous state (Cabrol et al. 2016). The remaining two individuals presented with pancreatitis. In both individuals, the p.Met952Thr variant was identified in a heterozygous state along with additional variants in other genes including an intronic heterozygous variant in the PRSS1 gene and a homozygous variant in the SPINK1 gene (Keiles et al. 2006; Schneider et al. 2011). The p.Met952Thr variant was present in one of 274 controls (Wilschanski et al. 2006; Schneider et al. 2011; Martinez et al. 2014) and is also reported at a frequency of 0.00058 in the European (non-Finnish) population of the Exome Aggregation Consortium, including one individual with the variant in a homozygous state. This variant has not been reported in individuals presenting with classic CF and is thought to be associated with a mild CF phenotype when present in trans with a second pathogenic variant (Schneider et al. 2011). Another variant at the same amino acid position (p. Met952Ile) has also been identified in probands with CFTR-related disorders (Uzun et al. 2005; Steiner et al. 2011). Based on the collective evidence, the p.Met952Thr variant is classified as likely pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mayo Clinic Laboratories, Mayo Clinic	RCV000587345	SCV001715963	uncertain significance	not provided	2023-01-23	criteria provided, single submitter	clinical testing	PP3, PM2
CeGaT Center for Human Genetics Tuebingen	RCV000587345	SCV002062781	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000046702	SCV002573832	uncertain significance	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3, PM5, PP3, BS2
Ambry Genetics	RCV000046702	SCV002745835	uncertain significance	Cystic fibrosis	2023-06-16	criteria provided, single submitter	clinical testing	The p.M952T variant (also known as c.2855T>C), located in coding exon 17 of the CFTR gene, results from a T to C substitution at nucleotide position 2855. The methionine at codon 952 is replaced by threonine, an amino acid with similar properties. This variant has been described in individuals with congenital bilateral absence of the vas deferens (CBAVD) who were also heterozygous for p.F508del; however, the phase of the variants was not confirmed (Mak V et al. JAMA, 1999 Jun;281:2217-24; Casals T et al. Hum. Reprod., 2000 Jul;15:1476-83). In addition, this variant was reported in trans with a multi-exon deletion in an individual with aquagenic palmar keratoderma and elevated sweat chloride levels (Cabrol C et al. Acta Derm. Venereol., 2016 08;96:848-9). This variant was also reported in a patient with familial chronic pancreatitis who was homozygous for a pathogenic SPINK1 vairant (Schneider A et al. Gastroenterology, 2011 Jan;140:162-71). This variant has also been described in control and general populations (Martinez B et al. J. Hum. Genet., 2014 Apr;59:206-10; Grangeia A et al. Pulmonology Mar;24:3-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000587345	SCV005197462	uncertain significance	not provided	2023-06-27	criteria provided, single submitter	clinical testing