rs397508267

Positions:

• chr7-117590353-A-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.1680A>C​(p.Arg560Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R560K) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CFTR NM_000492.4 missense, splice_region
• Scores: Splicing: ADA: 0.003127
• Clinical Significance: Pathogenic reviewed by expert panel P:8 O:1
• Conservation: PhyloP100: 2.63

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.

• PM1: In a helix (size 13) in uniprot entity CFTR_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117587833-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 7-117590353-A-C is Pathogenic according to our data. Variant chr7-117590353-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 53339.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117590353-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1680A>C	p.Arg560Ser	missense_variant, splice_region_variant	13/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1680A>C	p.Arg560Ser	missense_variant, splice_region_variant	13/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250272 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450264 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 721232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 20, 2021	The p.R560S pathogenic mutation (also known as c.1680A>C), located in coding exon 13 of the CFTR gene, results from a adenine to cysteine substitution at nucleotide position 1680. This variant impacts the first base pair of coding exon 13. The arginine at codon 560 is replaced by serine, an amino acid with dissimilar properties. This alteration has been detected in the homozygous state, and in a compound heterozygous state with the CFTR F508del mutation, in multiple individuals diagnosed with cystic fibrosis (Kraemer R et al. Pediatr Res, 1998 Dec;44:920-6; Claustres M et al. Hum Mutat, 2000;16:143-56; Malone G et al. Hum Mutat, 1998;11:152-7). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 22, 2022	Variant summary: CFTR c.1680A>C (p.Arg560Ser) 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 allele was found at a frequency of 4e-06 in 250272 control chromosomes. c.1680A>C has been reported in the literature as a biallelic homozygous or compound heterozygous genotype in multiple individuals affected with Cystic Fibrosis (example, Kraemer_1998, Malone_1998, Claustres_2000, McCague_2019, Awatade_2019). 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 (Awatade_2019). The most pronounced variant effect affects CFTR protein processing, totally abrogating the production of its mature form and no function as a chloride channel with no ability of the modulators to rescue CFTR processing or function. Three clinical diagnostic laboratories, one expert panel (CFTR2) and a database (CFTR-France) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 07, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Aug 31, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 3 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS1, PS3, PM1, PM2_SUP, PM3, PM5_STR, PP3 -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2023

Published functional studies demonstrate a damaging effect: absent chloride transport detected and absent expression of mature protein (PMID: 30030066, 23891399); Reported in homozygous state or with a second, pathogenic CFTR variant in individuals with cystic fibrosis; however, additional clinical and segregation information was not included (PMID: 10923036, 9482579); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23891399, 9482579, 30030066, 10923036, 15463917) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.6	D;.;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Uncertain	0.0030	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.99
MutPred		0.99		Loss of methylation at R560 (P = 0.0289);.;.;.;
MVP		1.0
MPC		0.016
ClinPred		1.0	D
GERP RS		3.6
Varity_R		1.0
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0031
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508267; hg19: chr7-117230407;