VCV000053180.3 - ClinVar

NM_000492.4(CFTR):c.1075_1079delinsAAAAA (p.Gln359_Thr360delinsLysLys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000492.4(CFTR):c.1075_1079delinsAAAAA (p.Gln359_Thr360delinsLysLys)

Variation ID: 53180 Accession: VCV000053180.3

Type and length

Indel, 5 bp

Location

Cytogenetic: 7q31.2 7: 117540305-117540309 (GRCh38) [ NCBI UCSC ] 7: 117180359-117180363 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 25, 2018	Dec 30, 2023	Aug 8, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000492.4:c.1075_1079delinsAAAAA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000483.3:p.Gln359_Thr360delinsLysLys	missense
NM_000492.3:c.1075_1079delCAAACinsAAAAA
NC_000007.14:g.117540305_117540309delinsAAAAA
NC_000007.13:g.117180359_117180363delinsAAAAA
NG_016465.4:g.79522_79526delinsAAAAA
LRG_663:g.79522_79526delinsAAAAA
LRG_663t1:c.1075_1079delinsAAAAA	LRG_663p1:p.Gln359_Thr360delinsLysLys

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000007.14:117540304:CAAAC:AAAAA

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA326387 dbSNP: rs397508152 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CFTR		-	-	GRCh38 GRCh37	3826	5201

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cystic fibrosis	Pathogenic (2)	criteria provided, single submitter	Feb 23, 2021	RCV000577797.2
Bronchiectasis with or without elevated sweat chloride 1	Pathogenic (1)	criteria provided, single submitter	Aug 8, 2023	RCV003473443.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Feb 23, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Cystic fibrosis Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001482265.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021	Publications: PubMed (17) PubMed: 9917439‚ 15371903‚ 7539210‚ 7525963‚ 16049310‚ 12151438‚ 12007216‚ 15948195‚ 9788722‚ 18456578‚ 11388756‚ 23974870‚ 7679367‚ 27214204‚ 28546993‚ 32429104‚ 30033373 Comment: Variant summary: CFTR c.1075_1079delinsAAAAA (p.Gln359_Thr360delinsLysLys) results in an in-frame deletion-insertion that is predicted to delete two amino acids from the protein and insert two new … (more) Variant summary: CFTR c.1075_1079delinsAAAAA (p.Gln359_Thr360delinsLysLys) results in an in-frame deletion-insertion that is predicted to delete two amino acids from the protein and insert two new amino acids. The variant allele was found at a frequency of 2.2e-05 in 277156 control chromosomes, absent in approximately 276736 alleles in the gnomAD database and reported at a frequency of 0.017 in alleles of Jewish Georgian origin (Shoshani_1993). c.1075_1079delinsAAAAA has been reported in the literature in multiple individuals affected with Cystic Fibrosis (example, Shoshani_1993, Wilschanski_1999, Bobadilla_2002, Sugarman_2004, Heim_2004, Chevalier-Porst_1994, Heim_2001, Petreska_1998, Schrijver_2005, Sosnay_2013, Quint_2005, Salinas_2016, Behar_2017, Mei-Zahav_2018, Petrova_2020). It has been observed as part of a multinucleotide variation, that is variably annotated either as Q359K/T360K, p.[Gln359Lys;Thr360Lys], c.[1075C>A;1079C>A], or c.1075_1079delCAAACinsAAAAA or p.Gln359_Thr360delinsLysLys. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in intermediate disruption in processing (Sosnay_2013). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Aug 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bronchiectasis with or without elevated sweat chloride 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004213436.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
not provided (-)	no classification provided Method: literature only	CFTR-related disorders Affected status: yes Allele origin: germline	ClinVar Staff, National Center for Biotechnology Information (NCBI) Accession: SCV000679075.1 First in ClinVar: Jan 25, 2018 Last updated: Jan 25, 2018	Publications: PubMed (1) PubMed: 18456578

Comment:

Variant summary: CFTR c.1075_1079delinsAAAAA (p.Gln359_Thr360delinsLysLys) results in an in-frame deletion-insertion that is predicted to delete two amino acids from the protein and insert two new amino acids. The variant allele was found at a frequency of 2.2e-05 in 277156 control chromosomes, absent in approximately 276736 alleles in the gnomAD database and reported at a frequency of 0.017 in alleles of Jewish Georgian origin (Shoshani_1993). c.1075_1079delinsAAAAA has been reported in the literature in multiple individuals affected with Cystic Fibrosis (example, Shoshani_1993, Wilschanski_1999, Bobadilla_2002, Sugarman_2004, Heim_2004, Chevalier-Porst_1994, Heim_2001, Petreska_1998, Schrijver_2005, Sosnay_2013, Quint_2005, Salinas_2016, Behar_2017, Mei-Zahav_2018, Petrova_2020). It has been observed as part of a multinucleotide variation, that is variably annotated either as Q359K/T360K, p.[Gln359Lys;Thr360Lys], c.[1075C>A;1079C>A], or c.1075_1079delCAAACinsAAAAA or p.Gln359_Thr360delinsLysLys. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in intermediate disruption in processing (Sosnay_2013). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients.	Petrova NV	Genes	2020	PMID: 32429104
The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews.	Mei-Zahav M	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2018	PMID: 30033373
Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening.	Behar DM	Molecular genetics & genomic medicine	2017	PMID: 28546993
Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California.	Salinas DB	PloS one	2016	PMID: 27214204
Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene.	Sosnay PR	Nature genetics	2013	PMID: 23974870
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.	Castellani C	Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society	2008	PMID: 18456578
Genotyping microarray for the detection of more than 200 CFTR mutations in ethnically diverse populations.	Schrijver I	The Journal of molecular diagnostics : JMD	2005	PMID: 16049310
Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening.	Quint A	American journal of medical genetics. Part A	2005	PMID: 15948195
CFTR mutation distribution among U.S. Hispanic and African American individuals: evaluation in cystic fibrosis patient and carrier screening populations.	Sugarman EA	Genetics in medicine : official journal of the American College of Medical Genetics	2004	PMID: 15371903
Analysis by mass spectrometry of 100 cystic fibrosis gene mutations in 92 patients with congenital bilateral absence of the vas deferens.	Wang Z	Human reproduction (Oxford, England)	2002	PMID: 12151438
Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening.	Bobadilla JL	Human mutation	2002	PMID: 12007216
Improved detection of cystic fibrosis mutations in the heterogeneous U.S. population using an expanded, pan-ethnic mutation panel.	Heim RA	Genetics in medicine : official journal of the American College of Medical Genetics	2001	PMID: 11388756
Clinical and genetic risk factors for cystic fibrosis-related liver disease.	Wilschanski M	Pediatrics	1999	PMID: 9917439
Molecular basis of cystic fibrosis in the Republic of Macedonia.	Petreska L	Clinical genetics	1998	PMID: 9788722
CFTR haplotype analysis reveals genetic heterogeneity in the etiology of congenital bilateral aplasia of the vas deferens.	Rave-Harel N	American journal of human genetics	1995	PMID: 7539210
Mutation analysis in 600 French cystic fibrosis patients.	Chevalier-Porst F	Journal of medical genetics	1994	PMID: 7525963
A new mutation in the CFTR gene, composed of two adjacent DNA alterations, is a common cause of cystic fibrosis among Georgian Jews.	Shoshani T	Genomics	1993	PMID: 7679367
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Text-mined citations for rs397508152 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 30, 2023

ClinVar Genomic variation as it relates to human health

NM_000492.4(CFTR):c.1075_1079delinsAAAAA (p.Gln359_Thr360delinsLysLys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397508152 ...