rs397508736

Positions:

• chr7-117534280-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The ENST00000003084.11(CFTR):​c.494T>C​(p.Leu165Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000429 in 1,398,736 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L165F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: CFTR ENST00000003084.11 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 O:1
• Conservation: PhyloP100: 7.27

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 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in ENST00000003084.11
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 7-117534280-T-C is Pathogenic according to our data. Variant chr7-117534280-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 53976.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117534280-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.494T>C	p.Leu165Ser	missense_variant	5/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.494T>C	p.Leu165Ser	missense_variant	5/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000429 AC: 6 AN: 1398736 Hom.: 0 Cov.: 24 AF XY: 0.00000572 AC XY: 4 AN XY: 699394

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000568

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 09, 2024	Variant summary: CFTR c.494T>C (p.Leu165Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 249460 control chromosomes. c.494T>C has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Cystic Fibrosis enrolled in the Clinical and Functional Translation of CFTR (CFTR2) project (example, McCague_2019). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 30888834). ClinVar contains an entry for this variant (Variation ID: 53976). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	research	CFTR2	Dec 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 22, 2024	The p.L165S pathogenic mutation (also known as c.494T>C), located in coding exon 5 of the CFTR gene, results from a T to C substitution at nucleotide position 494. The leucine at codon 165 is replaced by serine, an amino acid with dissimilar properties. This variant has been identified in the homozygous state and/or in conjunction with other CFTR variant(s) in individual(s) who met clinical criteria for cystic fibrosis; in at least one instance, the variants were identified in trans (Calcedo R et al. Hum Gene Ther Clin Dev, 2013 Sep;24:108-15; Gaitch N et al. Pancreatology Apr;2016:515-22; De Wachter E et al. Orphanet J Rare Dis, 2017 Aug;12:142). This variant has also been reported in multiple individuals with an elevated sweat chloride level and has <10% of wild type function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 05/20/2024; Raraigh KS et al. Am J Hum Genet, 2018 Jun;102:1062-1077). 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 variant is interpreted as a disease-causing mutation. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.0	M;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.1	D;.;.;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		1.0	D;.;.;.
Vest4		0.99
MutPred		0.94		Gain of disorder (P = 0.0017);Gain of disorder (P = 0.0017);Gain of disorder (P = 0.0017);Gain of disorder (P = 0.0017);
MVP		1.0
MPC		0.014
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.92
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397508736; hg19: chr7-117174334;