rs144476686

Positions:

chr7-117540188-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBS2_Supporting

The NM_000492.4(CFTR):c.958T>G(p.Leu320Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000273 in 1,614,098 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 3 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:2

Conservation

PhyloP100: 0.815

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 65 pathogenic changes around while only 10 benign (87%) in NM_000492.4

BP4

Computational evidence support a benign effect (MetaRNN=0.017049223).

BS2

High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.958T>G	p.Leu320Val	missense_variant	8/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.958T>G	p.Leu320Val	missense_variant	8/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000633

AC:

159

AN:

251284

Hom.:

AF XY:

0.000515

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00665

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.000259

AC:

379

AN:

1461812

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

172

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.00723

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000401

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000445

Hom.:

Bravo

AF:

0.000638

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 11, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 05, 2024	The CFTR c.958T>G (p.Leu320Val) variant has been reported in the published literature in individuals diagnosed with cystic fibrosis (CF) (PMID: 15858154 (2005), 30134826 (2018)) and atypical CF (PMID: 28546993 (2017)). The variant has also been reported in individuals with pancreatitis (PMID: 17003641 (2006), 18687795 (2008), 20460946 (2010), 30134826 (2018)), rhinosinusitis (PMID: 30134826 (2018)), and in an individual with Bohring-Opitz Syndrome (PMID: 26364555 (2015)). In a newborn screening study, the variant was identified as a non-causative variant for CF, but it could not rule out other CF-related disorders (PMID: 27214204 (2016)). The frequency of this variant in the general population, 0.0066 (68/10364 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	The CFTR c.958T>G; p.Leu320Val variant (rs144476686) is historically considered to be mildly pathogenic due to its prevalence in individuals affected with congenital bilateral absence of vas deferens, pancreatitis, and other CFTR-related disorders (Sick Kids CFTR database, Dorfman 2010, Keiles 2006, Lucarelli 2010, Masson 2013, Pelletier 2010, Salinas 2016, Shrijver 2005, Schwartz 2009). However, this variant is reported as a variant of uncertain significance by multiple laboratories in ClinVar (Variation ID: 35894), and is found in the general population with an overall allele frequency of 0.058% (163/282684 alleles, including 2 homozygotes) in the Genome Aggregation Database. The leucine at codon 320 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.545). Current evidence indicates that this variant, when present with a pathogenic CFTR variant on the opposite chromosome, is not associated with classic cystic fibrosis. However, it remains uncertain whether it may contribute to the clinical phenotype in individuals with milder CFTR-related disease (e.g., an isolated presentation of pancreatitis, congenital bilateral absence of the vas deferens, or mild lung disease). References: Sick Kids CFTR database link to L320V: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=174 Dorfman R et al. Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? Clin Genet. 2010 77(5):464-73. PMID: 20059485 Keiles S and Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641 Lucarelli M et al. A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation. Genet Med. 2010 12(9):548-55. PMID: 20706124 Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 8(8):e73522. PMID: 23951356 Pelletier A et al. CFTR gene mutation in patients with apparently idiopathic pancreatitis: lack of phenotype-genotype correlation. Pancreatology. 2010 10(2-3):158-64. PMID: 20460946 Salinas DB et al. Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California. PLoS One. 2016 May 23;11(5):e0155624. PMID: 27214204 Schrijver I et al. Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum. J Mol Diagn. 2005 7(2):289-99. PMID: 15858154 Schwartz KM et al. Identification of cystic fibrosis variants by polymerase chain reaction/oligonucleotide ligation assay. J Mol Diagn. 2009 May;11(3):211-5. PMID: 19324992 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2024	- -

Cystic fibrosis

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 06, 2024	The p.L320V variant (also known as c.958T>G), located in coding exon 8 of the CFTR gene, results from a T to G substitution at nucleotide position 958. The leucine at codon 320 is replaced by valine, an amino acid with highly similar properties. This alteration accounted for one cystic fibrosis (CF) allele in a cohort of Hispanic individuals with a clinical diagnosis of CF; specific clinical data and a pathogenic mutation in trans were not described (Schrijver I et al. J Mol Diagn. 2005;7(2):289-299). In another study, p.L320V was identified in a patient with idiopathic pancreatitis and was classified as causing a variable phenotype, including congenital absence of the vas deferens, chronic pancreatitis, or bronchiectasis (Pelletier AL et al. Pancreatology. 2010;10(2-3):158-164). In a retrospective study of newborns with positive newborn screening by immunoreactive trypsinogen, children carrying p.L320V in trans with a pathogenic mutation did not meet criteria for classic CF at follow-up (2 to 6 years); however, CFTR-related disorders were not ruled out (Salinas DB et al. PLoS ONE, 2016 May;11:e0155624; personal communication with Dr. Salinas). This alteration was also identified in an individual with an elevated sweat chloride and chronic pancreatitis. This individual also carried L997F however phase was not described (Sofia VM et al. Mol Med, 2018 07;24:38). Based on available evidence to date, this variant is unlikely to be causative of classic CF; however, its contribution to the development of a CFTR-related disorder is uncertain. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 20, 2022	- -

CFTR-related disorder

Uncertain:2

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 28, 2024	The CFTR c.958T>G variant is predicted to result in the amino acid substitution p.Leu320Val. The literature cites conflicting interpretations for this variant. In a series of 13 patients with the p.Leu320Val variant, none presented with pancreatic insufficiency (Salinas et al. 2016. PubMed ID: 27214204). Another group recently reported an additional patient with the c.958T>G variant without pancreatic insufficiency (Supplementary Table 1 in Saferali et al 2022. PubMed ID: 34996830). However, this variant has also been reported in two compound heterozygous individuals with cystic fibrosis (Schrijver et al. 2005. PubMed ID: 15858154; Lucarelli et al. 2010. PubMed ID: 20706124). This variant is reported in 0.66% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, and two homozygous individuals have been documented. Due to conflicting literature reports and the lack of conclusive family and functional studies, the clinical significance of the c.958T>G (p.Leu320Val) variant is currently uncertain. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 01, 2024

Variant summary: CFTR c.958T>G (p.Leu320Val) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 251284 control chromosomes, including 2 homozygotes, predominantly at a frequency of 0.002 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing CFTR-Related Diseases (0.00063 vs 0.013), allowing no conclusion about variant significance. c.958T>G has been reported in the literature in studies of individuals undergoing CFTR gene sequencing for CFTR-spectrum disorders such as idiopathic chronic pancreatitis, atypical CF phenotypes, and infertility/CBAVD (examples: Lucarelli_2010, Dorfman_2010, Pelletier_2010, Schrijver_2005, Keiles_2006, Schwartz_2009, Audrezet_2008, Masson_2013, Behar_2017) and in one case of an individual with Bohring-Opitz syndrome who harbored a disruptive frameshift mutation in the causative ASXL1 gene along with this variant and the pathogenic CFTR variant, p.F508del (Dangiolo_2015). However, the variant has also been reported in multiple individuals who carried a second CF-causing variant in trans and had a positive newborn screen for IRT, but were followed for 2-6 years and had no reported clinical CF phenotype (e.g. Salinas_2016). This finding suggests a benign role for the variant in association with CF, however other CFTR-related disorders could not be ruled out (e.g. Salinas_2016). In addition, the CFTR2 database reports the variant as non-CF causing in association with CF, stating that most individuals with this variant (combined with another CF-causing variant) will be healthy, although a small number of individuals may develop mild symptoms or be diagnosed with a CFTR-related disorder (CFTR-RD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18687795, 15858154, 17003641, 20059485, 20706124, 20460946, 19324992, 23951356, 27214204, 28465863, 28546993, 30134826, 26364555, 31036917, 32773111, 34583889). ClinVar contains an entry for this variant (Variation ID: 35894). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hereditary pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Apr 04, 2021

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 29, 2024

- -

Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 28, 2023

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;.;.;T;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.017

T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.33

N;.;.;.;N

PrimateAI

Benign

0.37

PROVEAN

Benign

0.39

N;.;.;N;.

REVEL

Uncertain

0.55

Sift

Benign

0.58

T;.;.;T;.

Sift4G

Benign

0.12

T;.;.;T;.

Polyphen

0.17

B;.;.;.;.

Vest4

0.83

MVP

1.0

MPC

0.0041

ClinPred

0.059

GERP RS

1.2

Varity_R

0.19

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over