7-117590377-G-T

Variant names:

• chr7-117590377-G-T
• rs397508275
• NM_000492.4:c.1704G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PP2 PP3_Strong

The NM_000492.4(CFTR):​c.1704G>T​(p.Leu568Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000758 in 1,451,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L568L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 0.197
• Publications: 4 publications found

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]

CFTR Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 18 uncertain in NM_000492.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1704G>T	p.Leu568Phe	missense_variant	Exon 13 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1704G>T	p.Leu568Phe	missense_variant	Exon 13 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000758 AC: 11 AN: 1451032 Hom.: 0 Cov.: 30 AF XY: 0.00000554 AC XY: 4 AN XY: 721718

African (AFR) AF: 0.00 AC: 0 AN: 33244

American (AMR) AF: 0.00 AC: 0 AN: 44386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25620

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39376

South Asian (SAS) AF: 0.00 AC: 0 AN: 86098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000906 AC: 10 AN: 1104322

Other (OTH) AF: 0.00 AC: 0 AN: 59670

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Uncertain:3 Other:1

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 25, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This CFTR variant (rs397508275) has been observed in the heterozygous state in males with congenital absence of the vas deferens, but has not been identified in patients with classic cystic fibrosis to our knowledge. It is absent from two large population datasets and while it is present in ClinVar, no classification is provided. Leu568 is the first residue of the highly conserved Walker B ATP-binding motif in the first nucleotide binding domain of CFTR. This suggests that this substitution may be functionally signficant, however no functional studies have been performed to our knowledge. Of three bioinformatics tools queried, two predict that this substitution would probably be damaging and the third predicts that it would be tolerated. The leucine at this position is highly evolutionarily conserved among the species assessed. Due to the lack of functional data, we consider the clinical significance of c.1704G>T to be uncertain at this time. -

Jun 10, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L568F variant (also known as c.1704G>T), located in coding exon 13 of the CFTR gene, results from a G to T substitution at nucleotide position 1704. The leucine at codon 568 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was observed in individuals diagnosed with congenital bilateral absence of the vas deferens (CBAVD) and/or idiopathic chronic pancreatitis; however, complete genotype information was not provided (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77; Audrezet MP et al. J Mol Diagn, 2008 Sep;10:424-34; Amato F et al. J Mol Diagn, 2012 Jan;14:81-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified Uncertain:1

Jun 30, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.1704G>T (p.Leu568Phe) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250456 control chromosomes in gnomAD. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1704G>T has been reported in the literature in individuals affected with Cystic Fibrosis or other CFTR-related diseases, however in most cases, strong evidence for causality could not be found (example: Amato_2012, Erdogan_2021, Liechti-Gallati_1999, Audrezet_2008, Masson_2013, Bozdogan_2021). In one Turkish individual affected with congenital absence of the vas deferens, c.1704G>T was at a compound heterozygous state along with a second pathogenic variant in CFTR (example: Dork_1997). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22020151, 18687795, 33572515, 9272157, 34860163, 10439967, 23951356). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (all VUS). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Uncertain	2.1	M;.;.;.
PhyloP100		0.20
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N;.;N;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D;.;D;.
Sift4G	Uncertain	0.0080	D;.;D;.
Polyphen		0.99	D;.;.;.
Vest4		0.94
MutPred		0.92		Gain of ubiquitination at K564 (P = 0.1575);.;.;.;
MVP		1.0
MPC		0.0055
ClinPred		0.86	D
GERP RS		1.5
Varity_R		0.65
gMVP		0.96
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397508275; hg19: chr7-117230431; COSMIC: COSV50049472; COSMIC: COSV50049472;