NM_000492.4(CFTR):c.3844T>C (p.Trp1282Arg) AND Cystic fibrosis

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 29, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000577632.10

Allele description [Variation Report for NM_000492.4(CFTR):c.3844T>C (p.Trp1282Arg)]

NM_000492.4(CFTR):c.3844T>C (p.Trp1282Arg)

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.3844T>C (p.Trp1282Arg)

HGVS:

NC_000007.14:g.117642564T>C
NG_016465.4:g.181781T>C
NM_000492.4:c.3844T>CMANE SELECT
NP_000483.3:p.Trp1282Arg
NP_000483.3:p.Trp1282Arg
LRG_663t1:c.3844T>C
LRG_663:g.181781T>C
LRG_663p1:p.Trp1282Arg
NC_000007.13:g.117282618T>C
NM_000492.3:c.3844T>C
P13569:p.Trp1282Arg

Protein change:

W1282R

Links:

UniProtKB: P13569#VAR_000261; dbSNP: rs397508616

NCBI 1000 Genomes Browser:

rs397508616

Molecular consequence:

NM_000492.4:c.3844T>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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Stt3A [Drosophila grimshawi]
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000679092	ClinVar Staff, National Center for Biotechnology Information (NCBI)	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002231222	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 29, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29504914, 30548586, 28492532
SCV002574040	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 5, 2022)	unknown	curation	PubMed (1) [See all records that cite this PMID]
SCV002621683	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 25, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 28340353, 29504914, 30548586, 31776420, 32429104, 32992607, 7681034 Citation Link

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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	literature only
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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (9)

Details of each submission

From ClinVar Staff, National Center for Biotechnology Information (NCBI), SCV000679092.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002231222.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

ClinVar contains an entry for this variant (Variation ID: 53820). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1282 of the CFTR protein (p.Trp1282Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 29504914, 30548586; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. 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. For these reasons, this variant has been classified as 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 Institute of Human Genetics, University of Leipzig Medical Center, SCV002574040.1

#	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_VSTR, PM5_STR, PP3, PP4

#	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, SCV002621683.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.W1282R pathogenic mutation (also known as c.3844T>C), located in coding exon 23 of the CFTR gene, results from a T to C substitution at nucleotide position 3844. The tryptophan at codon 1282 is replaced by arginine, an amino acid with dissimilar properties. This mutation was originally reported in an individual with cystic fibrosis; however, the presence of second CFTR variant was unknown (Ivaschenko TE et al. Hum Genet, 1993 Mar;91:63-5). The mutation has also been reported in multiple individuals with cystic fibrosis who had a pathogenic variant on the other chromosome (Ivanov M et al. BMC Med Genomics, 2018 02;11:13; Petrova NV et al. Clin Genet, 2019 03;95:444-447; Petrova NV et al. Genes (Basel), 2020 05;11(5):554; Petrova NV et al. Genes (Basel), 2020 9;11(10):1137). The variant also had minimal CFTR function in FRT cells (Phuan PW et al. Sci Rep, 2019 11;9:17640). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Liu F et al. Cell, 2017 03;169:85-95.e8). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: Sep 29, 2024

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