7-117603730-G-C
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PP2PP3_ModeratePP5
The NM_000492.4(CFTR):c.2856G>C(p.Met952Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M952T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Publications
- cystic fibrosisInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
- congenital bilateral absence of vas deferensInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary chronic pancreatitisInheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | MANE Select | c.2856G>C | p.Met952Ile | missense | Exon 17 of 27 | NP_000483.3 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CFTR | ENST00000003084.11 | TSL:1 MANE Select | c.2856G>C | p.Met952Ile | missense | Exon 17 of 27 | ENSP00000003084.6 | ||
| CFTR | ENST00000699602.1 | c.2856G>C | p.Met952Ile | missense | Exon 17 of 27 | ENSP00000514471.1 | |||
| CFTR | ENST00000426809.5 | TSL:5 | c.2766G>C | p.Met922Ile | missense | Exon 16 of 26 | ENSP00000389119.1 |
Frequencies
GnomAD3 genomes 0.0000789 AC: 12AN: 152170Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000796 AC: 20AN: 251352 AF XY: 0.000125 show subpopulations
GnomAD4 exome AF: 0.0000499 AC: 73AN: 1461728Hom.: 0 Cov.: 32 AF XY: 0.0000701 AC XY: 51AN XY: 727160 show subpopulations
Age Distribution
GnomAD4 genome 0.0000722 AC: 11AN: 152288Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8AN XY: 74466 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:7Uncertain:3Other:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.005%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.82 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.85 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000053580 /PMID: 9254864). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 15287992). A different missense change at the same codon (p.Met952Thr) has been reported to be associated with CFTR related disorder (ClinVar ID: VCV000053579 /PMID: 10875853). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Criteria applied: PM3_STR,PP3_MOD
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 952 of the CFTR protein (p.Met952Ile). This variant is present in population databases (rs151048781, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas deferens or cystic fibrosis (PMID: 10200050, 15070876, 15287992, 16272798, 16980811, 21520337, 23276700). 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: 53580). 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%. This variant disrupts the p.Met952 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 10875853), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
The CFTR c.2856G>C (p.Met952Ile) missense variant has been reported in at least six studies and is found in a total of ten individuals with CFTR-related disorders. The p.Met952Ile variant was identified in a compound heterozygous state in five individuals with congenital bilateral absence of the vas deferens (CBAVD), four of whom were identified with the p.Phe508del variant in trans (Uzun et al. 2005; Steiner et al. 2011). The p.Met952Ile was also identified in a heterozygous state in three individuals with cystic fibrosis, one individual with oligospermia, and one individual with CBAVD (Desgeorges et al. 1997; Onay et al. 1998; Gallati et al. 2009; Steiner et al. 2011; Křenková et al. 2013). The p.Met952Ile variant was absent from 415 controls but is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Met952Ile variant is classified as likely pathogenic for CFTR-related disorders, and has most commonly been reported in patients with CBAVD. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
The p.M952I variant (also known as c.2856G>C), located in coding exon 17 of the CFTR gene, results from a G to C substitution at nucleotide position 2856. The methionine at codon 952 is replaced by isoleucine, an amino acid with highly similar properties. CFTR p.M952I (c.2586G>A or c.2586G>C) was originally identified in an individual with severe pulmonary disease, pancreatic insufficiency, and an elevated sweat chloride level; a second CFTR alteration was not identified (Desgeorges M et al. Hum. Genet., 1997 Aug;100:279-83). This variant was also detected in conjunction with pathogenic CFTR mutations in individuals with idiopathic chronic pancreatitis and congenital bilateral absence of the vas deferens (CBAVD) (Uzun S et al. Tohoku J. Exp. Med., 2005 Dec;207:279-85; Ratbi I et al. Hum. Reprod. 2007;22(5):1285-91; Steiner B et al. Hum. Mutat. 2011 Aug;32(8):912-20; Akinsal EC et al. Andrologia, 2018 Feb; Rudnik-Schöneborn S et al. Hum Reprod, 2021 02;36:551-559). 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, this variant is unlikely to be causative of classic cystic fibrosis; however, it likely contributes to the development of a CFTR-related disorder. This alteration is thus classified as likely pathogenic.
not provided Pathogenic:5Uncertain:1
The CFTR c.2856G>C (p.Met952Ile) variant has been reported in multiple individuals with congenital bilateral absence of the vas deferens (CBAVD) who were also positive for a pathogenic variant in the CFTR gene known to be associated with cystic fibrosis (CF) (PMID: 15070876 (2004), 16272798 (2005), 17329263 (2007), 21520337 (2011), 29484681 (2018)). This variant has been reported in individuals with a diagnosis of CF, but a second CFTR variant was either not identified or the genotype of the affected individual was not reported (PMID: 9254864 (1997), 11446424 (2001), 15948195 (2005), 16617247 (2006), 28544683 (2017)). It has also been reported in individuals with classic CF who were positive for two other variants that prevent the synthesis of CFTR protein (PMID: 16980811 (2006), 23276700 (2013)). The frequency of this variant in the general population (0.00011, 13/113696 chromosomes (Genome Aggregation Database (http://gnomad.broadinstitute.org))) is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is deleterious. Based on the available information, this variant is classified as a likely pathogenic variant that is associated with CFTR-related disorders (CFTR-RD).
In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9254864, 9521595, 20021716, 18456578, 21520337, 34426522, 25033378, 28603918, 11446424, 29466940, 32003480, 16980811, 31005549, 35997436, 32773111, 15948195, 33572515, 15070876, 10200050, 26437683, 10601093, 15287992, 23276700, 20100616, 17975025, 16617247, 17329263, 29807875, 28544683, 34996830, 16272798, 33374015, 29484681, 27449771, Turkyilmaz2021[CaseReport], 34583889, 20797923, 37313453, 37823318, 38388235, 20977904, 10875853, 17003641, 14551163, 34949556, 27026144)
CFTR: PM3:Very Strong, PS1, PM2, PM5
Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:3
Variant summary: CFTR c.2856G>C (p.Met952Ile) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three 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-05 in 251352 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Congenital Bilateral Absence Of The Vas Deferens (8e-05 vs 0.013), allowing no conclusion about variant significance. c.2856G>C has been reported in the literature in compound heterozygosity with another pathogenic variant in multiple individuals affected with Congenital Bilateral Absence Of The Vas Deferens (CBAVD; e.g. de Meeus_1997, Claustres_2004, Dayangac_2004, Uzun_2005, Ratbi_2007, Steiner_2011, Akinsal_2018). These data indicate that the variant is very likely to be associated with CBAVD disease. The variant has also been reported in multiple individuals affected with cystic fibrosis, however in at least one case, two additional pathogenic mutations in CFTR were found (phase not specified; e.g. Kammesheidt_2006), and in others, a second pathogenic mutation was not reported, and therefore evidence for causality in these cases could not be established (e.g. Desgeorges_1997, Onay_1998, Quint_2005, Soltysova_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant that creates the same amino acid change has been reported as pathogenic for CBAVD by our lab (c.2856G>A). The following publications have been ascertained in the context of this evaluation (PMID: 29484681, 17975025, 15287992, 15070876, 9254864, 20797923, 20021716, 20100616, 16980811, 25033378, 9521595, 10601093, 15948195, 17329263, 33374015, 26437683, 28544683, 21520337, 16272798, 16617247, 10200050). 15 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: 12 submitters classified the variant as likely pathogenic/pathogenic while 3 classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic in association with CBAVD.
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:2
The CFTR c.2856G>C; p.Met952Ile variant (rs151048781) is reported in the literature in multiple individuals with congenital absence of the vas deferens (CBAVD), including in individuals with a second pathogenic CFTR variant (Dayangac 2004, Ratbi 2007, Steiner 2011, Uzun 2005). While this variant has also been reported in several individuals with cystic fibrosis (CF), one individual already carried two other pathogenic variants (Desgeorges 1997, Krenkova 2013). The p.Met952Ile variant is reported in ClinVar (Variation ID: 53580) and is found in the general population with an overall allele frequency of 0.008% (20/251352 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.817). Another variant at this codon (p.Met952Thr) has been reported in individuals with CBAVD and is considered pathogenic (Casals 2000, Gilljam 2004, Wilschanski 2006). Though it is unclear if the p.Met952Ile variant causes classic CF, due to its strong association with CBAVD, this variant is considered to be likely pathogenic. References: 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. Dayangac D et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2004 May;19(5):1094-100. PMID: 15070876. Desgeorges M et al. Cystic fibrosis in Lebanon: distribution of CFTR mutations among Arab communities. Hum Genet. 1997 Aug;100(2):279-83. PMID: 9254864. 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. Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. PMID: 23276700. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007 May;22(5):1285-91. PMID: 17329263. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;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.
CFTR-related disorder Pathogenic:1
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at