rs397508535

chr7-117611740-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000492.4(CFTR):c.3299A>C(p.Gln1100Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,462 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1 O:1
• Conservation: PhyloP100: 6.55

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 7-117611740-A-C is Pathogenic according to our data. Variant chr7-117611740-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53711.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, not_provided=1, Likely_pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3299A>C	p.Gln1100Pro	missense_variant	20/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3299A>C	p.Gln1100Pro	missense_variant	20/27	1	NM_000492.4	P2
	ENST00000456270.1	n.177+4489T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251108 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135700

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461462 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727020

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

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.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:5 Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 05, 2016	The p.Q1100P variant (also known as c.3299A>C), located in coding exon 20 of the CFTR gene, results from an A to C substitution at nucleotide position 3299. The glutamine at codon 1100 is replaced by proline, an amino acid with similar properties. This variant has been seen in two individuals from Spain and the Mediterranean who fulfilled criteria for a CF diagnosis; however, presence of a second alteration was not specified (Alonso MJ, et al. Ann. Hum. Genet. 2007 Mar; 71(Pt 2):194-201). In addition, this variant has been observed in conjunction with a second pathogenic mutation in two patients diagnosed with classic cystic fibrosis; however, phase was not specified (Kammesheidt A et al. Genet. Med. 2006 Sep; 8(9):557-62; Essawi et al. Dis. Markers 2015; Epub). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly in available vertebrate species. In addition, this alteration is predicted to be probably damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1100 of the CFTR protein (p.Gln1100Pro). This variant is present in population databases (rs397508535, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 16240056, 26208274, 27145507, 30232781). ClinVar contains an entry for this variant (Variation ID: 53711). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. This variant disrupts the p.Gln1100 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 23240968), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 14, 2023	Variant summary: CFTR c.3299A>C (p.Gln1100Pro) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Four of four 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 251108 control chromosomes. c.3299A>C has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Mota_2018, Siryani_2015, Alonso_2007, Chillon_1994). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: four submitters have classified the variant as likely pathogenic/pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 05, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 13, 2023	CFTR c.3299A>C has been identified in multiple individuals with elevated sweat chloride concentration and features of cystic fibrosis (CF) who also have a second CF-causing CFTR variant, although the phase of these variants has not been confirmed. This CFTR variant (rs397508535) is rare (<0.1%) in a large population dataset (gnomADv2.1.1: 1/251108 total alleles; 0.0004%; no homozygotes) and has been reported in ClinVar (Variation ID: 53711). A single peer-reviewed functional study indicates that this variant may impact CFTR trafficking. The glutamine residue at this position is evolutionarily conserved across most species assessed, but not fish. We consider CFTR c.3299A>C to be likely pathogenic. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

CFTR-related disorders Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2020

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.;.;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	2.0	M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.83	N;.;.;N;.
REVEL	Pathogenic	0.73
Sift	Benign	0.19	T;.;.;T;.
Sift4G	Uncertain	0.055	T;.;.;T;.
Polyphen		0.99	D;.;.;.;.
Vest4		0.93
MutPred		0.94		Loss of MoRF binding (P = 0.0692);.;.;.;.;
MVP		1.0
MPC		0.011
ClinPred		0.87	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.97

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: rs397508535; hg19: chr7-117251794;