rs193922511

chr7-117603687-T-G

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.2813T>G(p.Val938Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,613,998 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. V938L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 6.09

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 7-117603687-T-G is Pathogenic according to our data. Variant chr7-117603687-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35850.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.2813T>G	p.Val938Gly	missense_variant	17/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.2813T>G	p.Val938Gly	missense_variant	17/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251412 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135868

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461758 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000557 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 938 of the CFTR protein (p.Val938Gly). This variant is present in population databases (rs193922511, gnomAD 0.003%). This missense change has been observed in individuals with cystic fibrosis, unilateral congenital absence of the vas deferens, or bilateral absence of the vas deferens (PMID: 9272157, 17329263, 28603918). ClinVar contains an entry for this variant (Variation ID: 35850). 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 with a negative predictive value of 80%. This variant disrupts the p.Val938 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 9272157, 17329263, 28603918, 32777524, 36437957), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 22, 2022	The p.V938G variant (also known as c.2813T>G), located in coding exon 17 of the CFTR gene, results from a T to G substitution at nucleotide position 2813. The valine at codon 938 is replaced by glycine, an amino acid with dissimilar properties. This variant was identified in two individuals; one individual was homozygous and presented with congenital unilateral absence of the vas deferens (CUAVD) and asthma bronchiale. The other individual was heterozygous for this variant as well as a frameshift alteration and presented with congenital bilateral absence of the vas deferens (CBAVD) and a borderline sweat chloride level; the phase of these alterations was not provided (Dörk T et al. Hum. Genet. 1997 Sep; 100(3-4):365-77). In another study, this variant was observed in one individual with CBAVD and a gross deletion (Ratbi I et al. Hum. Reprod. 2007 May;22(5):1285-91). This amino acid position is 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 variant remains unclear. -

CFTR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 18, 2021

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 06, 2023

Variant summary: CFTR c.2813T>G (p.Val938Gly) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251512 control chromosomes (gnomAD), which does not exceed the estimated maximal expected allele frequency for a pathogenic CFTR variant causing CF/CFTR-RD/CBAVD. c.2813T>G has been reported in the literature in multiple individuals affected with Congenital Absence of the Vas Deferens (CBAVD and CUAVD)/infertility, once in a homozygous state, and others in a compound heterozygous state with other pathogenic CFTR variants (e.g., Dork_1997, Marcelli_2006, Robin_2007, Ratbi_2007, Rudnik-Schoneborn_2021). Because CBAVD/CUAVD is often found in patients with either one severe and one mildly pathogenic variant or two mildly pathogenic variants, the presence of this variant in CBAVD/CUAVD patients in trans with severe variants suggests that the variant may be a "mild" variant that contributes to CFTR-related disease. This variant has also been reported in patients screened for cystic fibrosis, idiopathic pancreatitis and other CFTR-related diseases, however not in well phenotyped cases of classic cystic fibrosis associated with pancreatic/pulmonary insufficiency (e.g., Sands_2015, Sofia_2016, De Wachter_2017, Bozdogan_2021, Nykamp_2021). At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in approximately 35% of normal chloride channel conductance relative to wild type (e.g., Bihler_2023 (bioRxiv, no PMID)). The following publications have been ascertained in the context of this evaluation (PMID: 33572515, 28830496, 18685558, 20059485, 9272157, 17175965, 34196078, 17329263, 17507277, 33374015, 26003066, 31674704, 27264265, 10755189, 26277102). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 3; likely pathogenic, n = 1; pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 16, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 19, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;D;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.5	M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D;.;.;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.65
MutPred		0.88		Loss of stability (P = 2e-04);.;.;.;.;
MVP		1.0
MPC		0.0074
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.96
gMVP		0.94

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: rs193922511; hg19: chr7-117243741;