NM_000492.4(CFTR):c.2855T>C (p.Met952Thr) AND Cystic fibrosis

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Dec 20, 2019
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000046702.22

Allele description [Variation Report for NM_000492.4(CFTR):c.2855T>C (p.Met952Thr)]

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

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

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

HGVS:

NC_000007.14:g.117603729T>C
NG_016465.4:g.142946T>C
NM_000492.4:c.2855T>CMANE SELECT
NP_000483.3:p.Met952Thr
NP_000483.3:p.Met952Thr
LRG_663t1:c.2855T>C
LRG_663:g.142946T>C
LRG_663p1:p.Met952Thr
NC_000007.13:g.117243783T>C
NM_000492.3:c.2855T>C

Protein change:

M952T

Links:

dbSNP: rs142773283

NCBI 1000 Genomes Browser:

rs142773283

Molecular consequence:

NM_000492.4:c.2855T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000074715	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 10875853, 17003641, 20977904, 25087612, 27026144, 29589582, 34949556, 10200050, 15070876, 15287992, 16272798, 16980811, 21520337, 23276700, 28492532
SCV000916182	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Dec 11, 2018)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16272798, 10376575, 10875853, 16840743, 20977904, 17003641, 24451227, 27026144, 21520337 Citation Link,
SCV001981590	CFTR2	reviewed by expert panel (Submitter's publication and website)	Uncertain significance (Dec 20, 2019)	germline	research	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV002573832	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 5, 2022)	unknown	curation	PubMed (1) [See all records that cite this PMID]
SCV002745835	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Uncertain significance (Jun 16, 2023)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 10376575, 10875853, 16840743, 20977904, 24451227, 25033378, 26354092, 27026144, 27673710, 29174009, 29589582, 31310009 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	1	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results.

Tabor HK, Auer PL, Jamal SM, Chong JX, Yu JH, Gordon AS, Graubert TA, O'Donnell CJ, Rich SS, Nickerson DA; NHLBI Exome Sequencing Project., Bamshad MJ.

Am J Hum Genet. 2014 Aug 7;95(2):183-93. doi: 10.1016/j.ajhg.2014.07.006. Epub 2014 Jul 31.

PubMed [citation]

PMID:: 25087612
PMCID:: PMC4129409

Reclassifying inconclusive diagnosis after newborn screening for cystic fibrosis. Moving forward.

Hatton A, Bergougnoux A, Zybert K, Chevalier B, Mesbahi M, Altéri JP, Walicka-Serzysko K, Postek M, Taulan-Cadars M, Edelman A, Hinzpeter A, Claustres M, Girodon E, Raynal C, Sermet-Gaudelus I, Sands D.

J Cyst Fibros. 2022 May;21(3):448-455. doi: 10.1016/j.jcf.2021.12.010. Epub 2021 Dec 21.

PubMed [citation]

PMID:: 34949556

See all PubMed Citations (25)

Details of each submission

From Invitae, SCV000074715.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000916182.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CFTR2, SCV001981590.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV002573832.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	curation	PubMed (1)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Ambry Genetics, SCV002745835.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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