rs397508759

chr7-117534363-G-Achr7-117534363-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):c.577G>A(p.Glu193Lys) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic,drug response (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 missense, splice_region
• Scores: Splicing: ADA: 0.9498
• Clinical Significance: Pathogenic; drug response reviewed by expert panel P:4 O:2
• Conservation: PhyloP100: 6.93

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 14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000492.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 7-117534363-G-A is Pathogenic according to our data. Variant chr7-117534363-G-A is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 54006.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.577G>A	p.Glu193Lys	missense_variant, splice_region_variant	5/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.577G>A	p.Glu193Lys	missense_variant, splice_region_variant	5/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250106 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135294

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1350814 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 678696

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:4 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 10, 2019	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to affect CFTR protein function (PMID: 9305991, 23891399, 19491324). This variant has been observed in several individuals affected with cystic fibrosis or congenital bilateral absence of the vas deferrens (PMID: 7544319, 7529962). ClinVar contains an entry for this variant (Variation ID: 54006). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 193 of the CFTR protein (p.Glu193Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. -
Pathogenic, reviewed by expert panel	research	CFTR2	Jul 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 27, 2023	Variant summary: CFTR c.577G>A (p.Glu193Lys) is located near a canonical splice site and results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250106 control chromosomes (gnomAD). c.577G>A has been reported in the literature in the compound heterozygous state in individuals affected with Cystic Fibrosis, including at least one case where it was found in trans with the pathogenic variant F508del, and in at least one individual with CBAVD (e.g. Brancolini_1995, Mercier_1995, Sofia_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Seibert_1997, Van Goor_2013). The variant results in approximately 30% of normal chloride transport activity and has a significantly reduced open probability and increased closed time compared to WT CFTR. The following publications have been ascertained in the context of this evaluation (PMID: 7544319, 7529962, 9305991, 30134826, 23891399). Four submitters, including the expert panel CFTR2, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -

ivacaftor response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.9	L;.;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.4	N;.;.;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.
Polyphen		0.97	D;.;.;.
Vest4		0.96
MutPred		0.86		Gain of ubiquitination at E193 (P = 0.0276);Gain of ubiquitination at E193 (P = 0.0276);Gain of ubiquitination at E193 (P = 0.0276);Gain of ubiquitination at E193 (P = 0.0276);
MVP		0.98
MPC		0.0057
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.80
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.80
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: rs397508759; hg19: chr7-117174417; COSMIC: COSV50044195; COSMIC: COSV50044195;