rs1800091

Variant names:

• chr7-117559587-A-C
• rs1800091
• NM_000492.4:c.1516A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-117559587-A-C
• chr7-117559587-A-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM5 PP2 PP3_Strong PP5

The NM_000492.4(CFTR):​c.1516A>C​(p.Ile506Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,328 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I506M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1 O:1
• Conservation: PhyloP100: 8.79
• Publications: 25 publications found

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]

CFTR-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 24 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117559589-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53278.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 7-117559587-A-C is Pathogenic according to our data. Variant chr7-117559587-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53275.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1516A>C	p.Ile506Leu	missense_variant	Exon 11 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.221+1146T>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1516A>C	p.Ile506Leu	missense_variant	Exon 11 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251282 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460328 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726550

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110772

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Uncertain:1 Other:1

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ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Apr 14, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Aug 05, 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.1516A>C (p.Ile506Leu) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251282 control chromosomes. c.1516A>C has been reported in the literature in individuals affected with Cystic Fibrosis (e.g. Strandvik_2001, Nunck_2020). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1517T>C, P.Ile506Thr), supporting the critical relevance of codon 506 to CFTR protein function. At least one publication reports experimental evidence that this variant results in significantly decreased chloride conductance compared to wildtype in vitro (e.g. Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 31916691, 11788090). ClinVar contains an entry for this variant (Variation ID: 53275). Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 disrupts the p.Ile506 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 7509683, 7525963, 11788090), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 53275). This missense change has been observed in individuals with cystic fibrosis (PMID: 11788090, 16678395). This variant is present in population databases (rs1800091, gnomAD 0.002%). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 506 of the CFTR protein (p.Ile506Leu). -

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I506L variant (also known as c.1516A>C), located in coding exon 11 of the CFTR gene, results from an A to C substitution at nucleotide position 1516. The isoleucine at codon 506 is replaced by leucine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals with a clinical diagnosis of cystic fibrosis and a known pathogenic mutation on the the other allele (Strandvik B et al. Genet Test, 2001;5:235-42). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Mar 07, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1516A>C; p.Ile506Leu variant (rs1800091) has been identified with a pathogenic severe variant on the opposite chromosome in two individuals with cystic fibrosis (Strandvik 2001). Both individuals were diagnosed later in adulthood and presented with high sweat chlorides, severe lung disease, and pancreatic sufficiency. This variant is also reported in ClinVar (Variation ID: 53275). It is only found on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism (V2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.886). Additionally, other amino acid substitutions at this codon (Met, Ser, Thr) have been reported in individuals with cystic fibrosis (Castellani 2008, Chevalier-Porst 1994, Deufel 1994). Based on available information, the p.Ile506Leu variant is considered to be likely pathogenic. References: Castellani C et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008 May;7(3):179-96. PMID: 18456578. Chevalier-Porst F et al. Mutation analysis in 600 French cystic fibrosis patients. J Med Genet. 1994 Jul;31(7):541-4. PMID: 7525963. Deufel A et al. Three novel mutations (I506S, S466X, 1651A-->T) in exon 10 of the cystic fibrosis transmembrane conductance regulator (CFTR) detected in patients of southern German descent. Hum Mutat. 1994;3(1):64-6. PMID: 7509683. Strandvik B et al. Spectrum of mutations in the CFTR gene of patients with classical and atypical forms of cystic fibrosis from southwestern Sweden: identification of 12 novel mutations. Genet Test. 2001 Fall;5(3):235-42. PMID: 11788090. -

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

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Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Feb 10, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

May 22, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.;.;D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.2	L;.;.;.;.
PhyloP100		8.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N;.;.;N;.
REVEL	Pathogenic	0.89
Sift	Benign	0.035	D;.;.;D;.
Sift4G	Uncertain	0.051	T;.;.;T;.
Polyphen		0.95	P;.;.;.;.
Vest4		0.84
MutPred		0.85		Loss of methylation at K503 (P = 0.0521);.;.;.;.;
MVP		1.0
MPC		0.014
ClinPred		0.80	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.95
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1800091; hg19: chr7-117199641;