rs1800086

chr7-117540282-C-Gchr7-117540282-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP6

The NM_000492.4(CFTR):c.1052C>G(p.Thr351Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,614,014 control chromosomes in the GnomAD database, including 2 homozygotes. 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. T351I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:12 B:2
• Conservation: PhyloP100: 7.43

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000492.4
• BP6: Variant 7-117540282-C-G is Benign according to our data. Variant chr7-117540282-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53174.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Likely_benign=1, Benign=1}. Variant chr7-117540282-C-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1052C>G	p.Thr351Ser	missense_variant	8/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1052C>G	p.Thr351Ser	missense_variant	8/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000183 AC: 46 AN: 251162 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135728

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000176 AC: 257 AN: 1461732 Hom.: 2 Cov.: 31 AF XY: 0.000171 AC XY: 124 AN XY: 727178

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74472

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000280

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:12 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:5 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Uncertain significance, criteria provided, single submitter	research	Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul	Oct 11, 2021	This imprecision led to the belief that this variant is pathogenic. Despite this variant has been classified and reclassified over the course of time as pathogenic and lately as likely pathogenic (by Mendelics and Invitae), new functional evidence has shown that this variant does not alter CFTR function even when located in the same allele (in cis) as NM_000492.4(CFTR):2552G>T; p.Arg851Leu) and in trans with the most common pathogenic variant p.Phe508del (NM_000492.4(CFTR):1521_1523delCTT). Although in a pathogenic range due to its very low frequency in public databases (1000 Genomes, GnomAd Exons, GnomAd Genomes, etc., in people from different ethnicities), the aminoacid change promoted by this missense variant is practically synonymous for both amino acids residues are polar uncharged (at physiological pH), conserving the hydroxyl group in the side chain of this amino acid, basically having absent to little impact in the CFTR protein. Also, there is another missense variant in the same nucleotide position which has been classified as having uncertain significance (NM_000492.4(CFTR):c.1052C>T; p.Thr351Ile). Besides, prediction tools do not fully agree when predicting the deleteriousness of this variant. Therefore, the controversial data existing to date regarding this variant leads to the classification of uncertain significance. Brief Medical History: the patient was diagnosed with NBS and treated with pancreatic enzymes until the age of 2-3 y.o. The mother decided to stop giving any medication. Since then, the patient presented normal thrive and growth, normal stature, and was eutrophic throughout her life, which would not be expected given the patient's genotype. The patient is now 22 y.o. and has no history of chronic lung infections nor exacerbations or any other features compatible with Cystic Fibrosis. Sweat chloride tests have always been within borderline range (30-59 mM). Also, the patient is pancreatic-sufficient. In January 2020, the patient provided stool samples. Fecal elastase-1 levels in feces samples are within the normal range of the assay, which is a biomarker of pancreatic exocrine sufficiency. Other biochemical and hematological measurements to verify liver function were also normal throughout the patient's life. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	May 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 07, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 06, 2022	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 351 of the CFTR protein (p.Thr351Ser). This variant is present in population databases (rs1800086, gnomAD 0.07%). This missense change has been observed in individual(s) with pancreatitis, congenital absence of the vas deferens (CAVD), and mild or atypical cysitic fibrosis (PMID: 2395135, 9272157, 15858154, 16128988, 23670503). ClinVar contains an entry for this variant (Variation ID: 53174). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 18, 2023	PP3, PM2 -

CFTR-related disorder Pathogenic:1 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	May 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 15, 2023	The CFTR c.1052C>G variant is predicted to result in the amino acid substitution p.Thr351Ser. This variant has been reported in the heterozygous state in an individual with idiopathic chronic pancreatitis, an individual with CBAVD, and in an individual with clinical manifestations consistent with the spectrum of CF (Masson. 2013. Table S1 PubMed ID: 23951356; Larriba et al. 2005 PubMed ID: 16128988; Schrijver et al. 2005. Table 1 PubMed ID: 15858154). This variant has also been reported in the compound heterozygous state with a p.Phe508del variant in an individual with CBAVD (Doerk et al. 1997. Table 3 PubMed ID: 9272157) and in the homozygous state (and in cis with another CFTR variant) in an individual with a CFTR-related disorder (Trujillano. 2013. Table S3 PubMed ID: 23687349). In one individual with CF, this variant was one of three identified, and was in cis with a p.Phe508del variant (Dal'Maso et al. 2013 Table 3 PubMed ID: 23670503). To our knowledge, no functional or family studies are available to confirm the pathogenicity of the c.1052C>G change. This variant is reported in 0.068% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117180336-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 28, 2023

Variant summary: CFTR c.1052C>G (p.Thr351Ser) results in a conservative amino acid change in 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 0.00019 in 251742 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00019 vs 0.013), allowing no conclusion about variant significance. c.1052C>G has been reported in the literature in individuals affected with Cystic Fibrosis, CBAVD, chronic pancreatitis and diffuse bronchiectasis, without strong evidence of causality (Mercier_1993, Dork_1997, Schrijver_2005, Bienvenu_2010, de Cid_2010, Dal Maso_2013, Masson_2013, Trujillano_2013, Grangeia_2018, Rispoli_2020, da Silva Filho_2021). These reports do not provide unequivocal conclusions about association of the variant with disease. At-least two co-occurrences in cis with other pathogenic variants have been reported (e.g. CFTR c.3484C>T, p.Arg1162X; CFTR c.1521_1523del, p.Phe508del) (Mercier_1993, Dal Maso_2013), providing supporting evidence for a benign role. One of these reports was in an obligate carrier father of an individual with CF (in cis with p.Arg1162X, Mercier_1993) while the other was in an individual reportedly affected with CF who harbored a non-informative genotype attributed to a synonymous variant (p.Pro1290=) in trans (in cis with p.Phe508del, Del Maso_2013). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20167849, 33572515, 23670503, 20059485, 9272157, 18716917, 29589582, 16128988, 23951356, 8477260, 25735457, 32185651, 15858154, 23687349, 32819855, 19812525). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance (n=9) and as benign (n=2) and Likely pathogenic without supporting evidence (n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hereditary pancreatitis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 31, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.3	M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N;.;.;N;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0070	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		0.95	P;.;.;.;.
Vest4		0.85
MutPred		0.82		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);
MVP		0.99
MPC		0.0052
ClinPred		0.21	T
GERP RS		5.3
Varity_R		0.80
gMVP		0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800086; hg19: chr7-117180336;