rs397508273

chr7-117590376-T-A

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.1703T>A(p.Leu568Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L568L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.65

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 7-117590376-T-A is Pathogenic according to our data. Variant chr7-117590376-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1703T>A	p.Leu568Ter	stop_gained	13/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1703T>A	p.Leu568Ter	stop_gained	13/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 04, 2023	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 53348). This variant is also known as c.1835T>A. This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 9067754). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu568*) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 27, 2016	The p.L568* pathogenic mutation (also known as c.1703T>A), located in coding exon 13 of the CFTR gene, results from a T to A substitution at nucleotide position 1703. This changes the amino acid from a leucine to a stop codon within coding exon 13. This mutation was identified in one individual with moderate pulmonary disease, pancreatic insufficiency, and elevated sweat chloride levels; p.F508del was also detected but the phase is not known (Macek M, et al. Hum. Mutat. 1997; 9(2):136-47). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2023	Variant summary: CFTR c.1703T>A (p.Leu568X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250456 control chromosomes. c.1703T>A has been reported in the literature in individuals affected with Cystic Fibrosis (eg. Macek_1997). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	41
Dann	Uncertain	0.99
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.96
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.30		Position offset: -23

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508273; hg19: chr7-117230430;