rs397508303

Variant names:

• chr7-117591958-CAAAACTA-C
• rs397508303
• NM_000492.4:c.1792_1798delAAAACTA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1792_1798delAAAACTA​(p.Lys598GlyfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 8.60

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117591958-CAAAACTA-C is Pathogenic according to our data. Variant chr7-117591958-CAAAACTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 53388.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117591958-CAAAACTA-C is described in Lovd as [Pathogenic]. Variant chr7-117591958-CAAAACTA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1792_1798delAAAACTA	p.Lys598GlyfsTer11	frameshift_variant	Exon 14 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1792_1798delAAAACTA	p.Lys598GlyfsTer11	frameshift_variant	Exon 14 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:5

Aug 03, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 11, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CFTR c.1792_1798delAAAACTA variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense meditated decay, which are commonly known mechanisms for CF. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Thr663fs). Mutation Taster predicts a damaging outcome for this variant. This variant was not found in 117990 control chromosomes, but has been identified in at least 7 CF patients with an average sweat chloride test of 119 mmol/L (CFTR2 database). In addition, at least one reputable database has classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 24, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes 7 nucleotides in exon 14 of the CFTR mRNA (c.1792_1798delAAAACTA), causing a frameshift at codon 598. This creates a premature translational stop signal (p.Lys598Glyfs*11) and is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CFTR are known to be pathogenic. This particular variant has been reported in the literature (PMID: 9298826, 16963320). This variant is also known as 1924del7 and c.1924_1930del. -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

CFTR-related disorder Pathogenic:1

May 20, 2019

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397508303; hg19: chr7-117232012;