rs121909021

chr7-117540276-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP5_Strong

The NM_000492.4(CFTR):c.1046C>T(p.Ala349Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000292 in 1,613,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A349P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:14
• 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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117540275-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 618892.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP5: Variant 7-117540276-C-T is Pathogenic according to our data. Variant chr7-117540276-C-T is described in ClinVar as [Uncertain_significance]. Clinvar id is 7172.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=14, Likely_pathogenic=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1046C>T	p.Ala349Val	missense_variant	8/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1046C>T	p.Ala349Val	missense_variant	8/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 251102 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135692

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.000212

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000308 AC: 450 AN: 1461564 Hom.: 0 Cov.: 31 AF XY: 0.000261 AC XY: 190 AN XY: 727078

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

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: 0.000374

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152110 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74294

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000120 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000709

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:3 Uncertain:14

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 14, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 349 of the CFTR protein (p.Ala349Val). This variant is present in population databases (rs121909021, gnomAD 0.02%). This missense change has been observed in individuals with CFTR-related diseases, including recurrent pancreatitis, cystic fibrosis (CF), CF-related metabolic syndrome, and congenital bilateral absence of the vas deferens (PMID: 15070876, 15638824, 17003641, 22094894, 25754095, 26671754). ClinVar contains an entry for this variant (Variation ID: 7172). 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 not expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 30046002). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The CFTR c.1046C>T; p.Ala349Val variant has been reported in patients diagnosed with congenital bilateral absence of vas deferens (Dayangac 2004) or pancreatitis (Keiles 2006), when found in-trans with pathogenic CFTR variants (Dayangac 2004). Functional studies show this variant to have approximately 45% of wild type function (Raraigh 2018). The observed variant has been submitted to ClinVar with conflicting interpretation of pathogenicity (Pathogenic/Likely Pathogenic/ Variant of Uncertain Significance). The p.Ala349Val variant is reported with the allele frequency (0.01%) in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Ala at position 349 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by PolyPhen2 and the residue is conserved across species. The amino acid change p.Ala349Val in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. According to Cystic fibrosis mutation database, the effect of homozygous mutation on this disorder is uncertain, hence the variant has been classified as a Variant of Uncertain Significance (VUS). -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 31, 2023	The p.A349V variant (also known as c.1046C>T), located in coding exon 8 of the CFTR gene, results from a C to T substitution at nucleotide position 1046. The alanine at codon 349 is replaced by valine, an amino acid with similar properties. This variant was identified in one individual with congenital bilateral absence of the vas deferens (CBAVD) and one individual with recurrent acute pancreatitis; both individuals were also heterozygous for a pathogenic mutation, but the phase is unknown (Dayangaç D et al. Hum. Reprod., 2004 May;19:1094-100; Sultan M et al. J. Pediatr. Gastroenterol. Nutr., 2012 May;54:645-50). In CFBE cells, this variant demonstrated 45% of wild type CFTR function (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
Uncertain significance, reviewed by expert panel	research	CFTR2	Oct 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 22, 2020	CFTR variant of uncertain clinical significance. See www.CFTR2.org for phenotype information. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 08, 2016	- -

not provided Pathogenic:1 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2022	Published functional studies demonstrate reduced, but not absent, CFTR function (Han 2018, Raraigh 2018); Identified in the single heterozygous state or with a second CFTR variant, phase unknown, in patients with cystic fibrosis or other CFTR-related disorders (Audrezet et al., 1993; Scotet et al., 2001; Dayangac et al., 2004; Keiles et al., 2006; Sultan et al., 2012; Wooldridge et al., 2015; Levy et al., 2016; McCague et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 8627844, 11933191, 16635477, 15024729, 19324992, 25304080, 25735457, 33500538, 30046002, 7683952, 17003641, 31036917, 25087612, 26671754, 23523379, 25754095, 11168024, 15070876, 15638824, 20100616, 22094894, 29669919, 30888834, 33922413, 19897426, 29805046, 34996830, 35652053, 36253274) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 08, 2023	The CFTR c.1046C>T; p.Ala349Val variant (rs121909021) has been reported in patients diagnosed with congenital bilateral absence of vas deferens (Dayangac 2004, Havasi 2010) or pancreatitis (Keiles 2006, Sultan 2010), when found in-trans with pathogenic CFTR variants (Dayangac 2004, Sultan 2012). Functional studies show this variant to have approximately 45% of wild type function (Raraigh 2018). This variant is reported in ClinVar (Variation ID: 7172). It is found in the general population with an overall allele frequency of 0.01% (32/282468 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.632). Due to its reported occurrence in CFTR-related disorders, the p.Ala349Val variant is classified as mildly pathogenic. References: Dayangac D et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2004 May;19(5):1094-100. PMID: 15070876. Havasi V et al. Association of cystic fibrosis genetic modifiers with congenital bilateral absence of the vas deferens. Fertil Steril. 2010 Nov;94(6):2122-7. PMID: 20100616. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Sultan M et al. Genetic prevalence and characteristics in children with recurrent pancreatitis. J Pediatr Gastroenterol Nutr. 2012 May;54(5):645-50. PMID: 22094894. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. PMID: 29805046. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 11, 2023	This variant has been reported in the published literature in individuals with pancreatic sufficient cystic fibrosis (PMID: 25754095 (2015)), pancreatitis (PMID: 17003641 (2006), 22094894 (2012)), congenital bilateral absence of the vas deferens (CBAVD) (PMID: 8627844 (1996), 15070876 (2004)), and CFTR-related metabolic syndrome (CRMS) (PMID: 26671754 (2016)). A functional assay found this variant showed decreased CFTR function compared to wild-type (PMID: 29805046 (2018)). The frequency of this variant in the general population, 0.00022 (28/128882 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 conflicting predictions that this variant is deleterious or 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	Mayo Clinic Laboratories, Mayo Clinic	Jun 29, 2022	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 02, 2023

Variant summary: CFTR c.1046C>T (p.Ala349Val) results in a non-conservative amino acid change located in the ABC transporter transmembrane region 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 0.00011 in 251726 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (0.00011 vs 0.013), allowing no conclusion about variant significance. c.1046C>T has been reported in the literature as a non-informative genotype in individuals ranging from a healthy carrier male, CBAVD, laboratory based CF genotyping cohorts, pancreatitis, pancreatically sufficient CF and cystic fibrosis transmembrane regulator-related metabolic syndrome with normal sweat chloride levels (example, Audrezet_1993, Schlegel_1996, Scotet_2001, Ravnik-Glavac_2002, Castaldo_2005, Lucarelli_2006, Sultan_2012, Wooldridge_2015, Schwartz_2009, Havasi_2010, Keiles_2006, Levy_2016, Tamura_2018, McCague_2019). In our conservative assessment, these data do not allow any conclusion about variant significance. Two publications reporting experimental evidence evaluating an impact on protein function were ascertained in the context of this evaluation. The most pronounced variant effect results in 30%-50% of normal CFTR activity with a categorization as indeterminate (Raraigh_2018, Han_2018). The following publications have been ascertained in the context of this evaluation (PMID: 11168024, 17003641, 15638824, 19324992, 11933191, 7683952, 16635477, 8627844, 22094894, 20100616, 25735457, 25754095, 29805046, 30046002, 29669919, 26671754, 30888834). 13 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic/pathogenic, n=4; VUS, n=9). 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 pathogenic. -

Hereditary pancreatitis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Apr 21, 2023

- -

Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 26, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	D;.;.;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.20	N;.;.;.;N
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.23	N;.;.;N;.
REVEL	Uncertain	0.63
Sift	Benign	0.17	T;.;.;T;.
Sift4G	Uncertain	0.0030	D;.;.;D;.
Polyphen		0.91	P;.;.;.;.
Vest4		0.49
MVP		1.0
MPC		0.0064
ClinPred		0.54	D
GERP RS		5.3
Varity_R		0.42
gMVP		0.81

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: rs121909021; hg19: chr7-117180330;