NM_000492.4(CFTR):c.3485G>T (p.Arg1162Leu) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Apr 2, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000726998.47

Allele description [Variation Report for NM_000492.4(CFTR):c.3485G>T (p.Arg1162Leu)]

NM_000492.4(CFTR):c.3485G>T (p.Arg1162Leu)

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.3485G>T (p.Arg1162Leu)

HGVS:

NC_000007.14:g.117627538G>T
NG_016465.4:g.166755G>T
NM_000492.4:c.3485G>TMANE SELECT
NP_000483.3:p.Arg1162Leu
NP_000483.3:p.Arg1162Leu
LRG_663t1:c.3485G>T
LRG_663:g.166755G>T
LRG_663p1:p.Arg1162Leu
NC_000007.13:g.117267592G>T
NM_000492.3:c.3485G>T
NM_000492.4:c.3485G>T
P13569:p.Arg1162Leu

Protein change:

R1162L

Links:

UniProtKB: P13569#VAR_000252; dbSNP: rs1800120

NCBI 1000 Genomes Browser:

rs1800120

Molecular consequence:

NM_000492.4:c.3485G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Fusinus longissimus voucher MNHN:IM:2007-32535 histone H3 gene, partial cds
Fusinus longissimus voucher MNHN:IM:2007-32535 histone H3 gene, partial cds
gi|1023301795|gb|KT754031.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000704812	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Uncertain significance (Aug 30, 2018)	germline	clinical testing	Citation Link,
SCV000883574	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Nov 10, 2023)	germline	clinical testing	Citation Link,
SCV001155243	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Dec 1, 2019)	germline	clinical testing	Citation Link,
SCV002009130	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002047286	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Aug 4, 2023)	unknown	clinical testing	PubMed (18) [See all records that cite these PMIDs] 15097853, 17489851, 24419263, 28603918, 12167682, 25824995, 25033378, 10923036, 17035430, 27022295, 23951356, 16481891, 33020115, 34405919, 34996830, 23974870, 26014425, 26467025
SCV005197468	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 13, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005369821	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 2, 2024)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	11	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis?

Casals T, Aparisi L, Martínez-Costa C, Giménez J, Ramos MD, Mora J, Diaz J, Boadas J, Estivill X, Farré A.

Pancreas. 2004 May;28(4):374-9.

PubMed [citation]

PMID:: 15097853

Contribution of the CFTR gene, the pancreatic secretory trypsin inhibitor gene (SPINK1) and the cationic trypsinogen gene (PRSS1) to the etiology of recurrent pancreatitis.

Tzetis M, Kaliakatsos M, Fotoulaki M, Papatheodorou A, Doudounakis S, Tsezou A, Makrythanasis P, Kanavakis E, Nousia-Arvanitakis S.

Clin Genet. 2007 May;71(5):451-7.

PubMed [citation]

PMID:: 17489851

See all PubMed Citations (19)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000704812.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	not provided	not provided	clinical testing	not provided

#	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		11	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000883574.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The CFTR c.3485G>T, p.Arg1162Leu variant (rs1800120) has not been associated with classic cystic fibrosis (Fanen 1992, Narzi 2007, Salinas 2016, Sosnay 2013, see link to CFTR database), but is found in several individuals with CFTR-related disorders, such as bronchiectasis and chronic pancreatitis (Casals 2004, Groman 2002, Lazaro 1999, Ziedalski 2006). This variant is listed in ClinVar (Variation ID: 256253), and is found in the general population with an overall allele frequency of 0.070% (198/282012 alleles) in the Genome Aggregation Database. The variant is enriched in pancreatitis patients tested by ARUP Laboratories compared to the general population (Genome Aggregation Database), with an odds ratio of 2.0 (95 percent CI: 1.2 to 3.4, adjusted p-value: 0.04). The arginine at position 1162 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.944). Although the p.Arg1162Leu variant is not expected to cause classical cystic fibrosis, when paired with a second pathogenic CFTR variant on the opposite chromosome, the p.Arg1162Leu variant may contribute to CFTR-related disorders, such as pancreatitis. References: Link to CFTR database: http://cftr.org/ Casals T et al. Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis? Pancreas. 2004; 28(4):374-9. PMID: 15097853. Fanen P et al. Molecular characterization of cystic fibrosis: 16 novel mutations identified by analysis of the whole cystic fibrosis conductance transmembrane regulator (CFTR) coding regions and splice site junctions. Genomics. 1992; 13(3):770-6. PMID: 1379210. Groman J et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002; 347(6):401-7. PMID: 12167682. Lazaro C et al. Missense mutations in the cystic fibrosis gene in adult patients with asthma. Hum Mutat. 1999; 14(6):510-9. PMID: 10571949. Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007; 72(1):39-46. PMID: 17594398. Salinas D et al. Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California. PLoS One. 2016; 11(5):e0155624. PMID: 27214204. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870. Ziedalski T et al. Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection. Chest. 2006; 130(4):995-1002. PMID: 17035430.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001155243.27

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

#	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		3	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009130.3

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

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002047286.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

The CFTR c.3485G>T (p.Arg1162Leu) variant has been reported in the published literature in an individual with cystic fibrosis (CF) without a second CFTR variant being identified (PMID: 27022295 (2016)). The variant has also been reported in an asymptomatic individual (PMID: 28603918 (2017), 17489851 (2007)), and in multiple individuals with non-classic CF (PMID: 12167682 (2002)) and CFTR-related disorders including pancreatitis (PMID: 15097853 (2004), 23951356 (2013), 25033378 (2014)) bronchiectasis (PMID: 17035430 (2006), 33020115 (2020)), and CBAVD (PMID: 16481891 (2006)). Functional studies indicate this variant does not affect the quantity of CFTR protein, and the chloride conductance was measured at 130% that of the wild type (PMID: 23974870 (2013)). This variant is not associated with classic CF but may be associated with mild symptoms or a CF-related disorder when a CF-causing mutation is present on the opposite chromosome (PMID: 23974870 (2013), 25824995 (2015)). The frequency of this variant in the general population, 0.0037 (10/2668 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.

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

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005197468.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	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 GeneDx, SCV005369821.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Classified as a non-CF-causing variant in a well curated database, however, may cause CFTR-RD in some cases (CFTR2); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27022295, 16481891, 23951356, 12167682, 18687795, 11788090, 19202204, 26474805, 23974870, 25824995, 17035430, 17594398, 21804385, 30230192, 18716917, 20812883, 27583671, 10571949, 36529661, 34405919, 34996830, D'Alcamo2022[CaseReport], 28603918, Andelkovic2018[CaseReport], 36670555, 33020115, 38388235, 38493004, 33572515, 37389024, 37253358, 37628659, Atli2023[CaseReport], 34949556, 35626323)

#	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

Last Updated: Oct 26, 2024

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