NM_000492.4:c.1680A>T

Variant names:

• chr7-117590353-A-T
• NM_000492.4:c.1680A>T

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>T​(p.Arg560Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. 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)
• Consequence: CFTR NM_000492.4 missense, splice_region
• Scores: Splicing: ADA: 0.005495
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 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-T is Pathogenic according to our data. Variant chr7-117590353-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1777899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1680A>T	p.Arg560Ser	missense_variant, splice_region_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.1680A>T	p.Arg560Ser	missense_variant, splice_region_variant	Exon 13 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:2

Jan 25, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.1680A>T (p.Arg560Ser) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. This results in the same amino acid change as a previously established pathogenic variant (c.1680A>C/p.Arg560Ser). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250272 control chromosomes (gnomAD). The variant has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Liechti-Gallati_1999, Claustres_2000, McCague_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, finding that the variant results in the loss of mature CFTR and no chloride transport (Van Goor_2014). The following publications have been ascertained in the context of this evaluation (PMID: 30888834, 23891399, 10923036, 10439967). ClinVar contains an entry for this variant (Variation ID: 1777899). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 03, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R560S pathogenic mutation (also known as c.1680A>T), located in coding exon 13 of the CFTR gene, results from a adenine to thymine 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 (Malone G et al. Hum Mutat, 1998;11:152-7; Kraemer R et al. Pediatr Res, 1998 Dec;44:920-6; Claustres M et al. Hum Mutat, 2000;16:143-56). This variant has 0% of wild type quantity and function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 08/02/2022) and in one published functional study (Van Goor F et al. J Cyst Fibros, 2014 Jan;13:29-36). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;D;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.89	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	0.0055
dbscSNV1_RF	Benign	0.094
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-117230407;