Submissions for variant NM_000492.4(CFTR):c.2758G>A (p.Val920Met)

gnomAD frequency: 0.00003  dbSNP: rs373885282

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000577642	SCV000788957	uncertain significance	Cystic fibrosis	2017-11-13	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000731224	SCV000859011	uncertain significance	not provided	2018-01-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000731224	SCV000885175	uncertain significance	not provided	2022-09-19	criteria provided, single submitter	clinical testing	The CFTR c.2758G>A; p.Val920Met variant (rs373885282) is reported in the literature in the compound heterozygous state with a second pathogenic or pathogenic-mild variant in individuals affected with cystic fibrosis or CFTR-related disorders (see link to cystic fibrosis mutation database, Claustres 2000, Cohn 2005, Trujillano 2013). However, this variant is also reported in individuals affected with CFTR-related disorders in the heterozygous state without a second pathogenic variant (Amato 2012, Bernardino 2003, Rene 2011), or with other variants that potentially explain the phenotype (Groman 2002, Masson 2013). This variant is reported in ClinVar (Variation ID: 53561), and is found in the general population with an overall allele frequency of 0.013% (36/282810 alleles, including a single homozygote) in the Genome Aggregation Database. The valine at codon 920 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.792). Due to conflicting information, the clinical significance of the p.Val920Met variant is uncertain at this time. References: Link to cystic fibrosis mutation database: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=398 Amato F et al. Extensive molecular analysis of patients bearing CFTR-related disorders. J Mol Diagn. 2012 Jan;14(1):81-9. PMID: 22020151. Bernardino AL et al. CFTR, PRSS1 and SPINK1 mutations in the development of pancreatitis in Brazilian patients. JOP. 2003 Sep;4(5):169-77. PMID: 14526128. Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-56. PMID: 10923036. Cohn JA et al. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat. 2005 Oct;26(4):303-7. PMID: 16134171. Groman JD et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002 Aug 8;347(6):401-7. PMID: 12167682. 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 Aug 8;8(8):e73522. PMID: 23951356. Rene C et al. p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study. Eur J Hum Genet. 2011 Jan;19(1):36-42. PMID: 20717170. Trujillano D et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet. 2013 Jul;50(7):455-62. PMID: 23687349.
Fulgent Genetics, Fulgent Genetics	RCV000765926	SCV000897346	uncertain significance	Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral aplasia of vas deferens from CFTR mutation	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781291	SCV000919204	uncertain significance	not specified	2024-07-08	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.2758G>A (p.Val920Met) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 252114 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (0.00014 vs 0.013), allowing no conclusion about variant significance. c.2758G>A has been reported in the literature in compound heterozygosity with p.F508del in individuals affected with Non-Classic Cystic Fibrosis or congenital absence of the vas deferens (Claustres_2000), with p.F508del and the 5T/13TG allele in an individual with Non-Classic Cystic Fibrosis (Groman_2002), and with 5T/13TG in an individual with a CFTR-related disorder (Trujillano_2013, Trujillano_2015). It has also been reported in individuals with chronic pancreatitis (Cohn_2005, Masson_2013), hyperechogenic fetal bowel (Rene_2011, deBecdelievre_2011), and in the heterozygous state without a second pathogenic variant specified in individuals with CFTR-related disorders (e.g. Amato_2012, Salinas_2023) as well as a healthy control individual (Steiner_2011). These data indicate that the variant may be associated with disease. 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: 22020151, 33083013, 10923036, 16134171, 12167682, 23951356, 20717170, 36409994, 21520337, 23687349, 26436105, 21184098). ClinVar contains an entry for this variant (Variation ID: 53561). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Mendelics	RCV000577642	SCV001137487	uncertain significance	Cystic fibrosis	2019-05-28	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000577642	SCV001424389	pathogenic	Cystic fibrosis		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000577642	SCV001822121	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000731224	SCV001986040	uncertain significance	not provided	2020-10-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with CFTR-related disorders such as pancreatitis and bronchiectasis (Bernardino 2003, Cohn 2005, Amato 2012); Observed with a pathogenic variant in individuals with cystic fibrosis, non-classic cystic fibrosis, and congenital absense of vas deferens in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Claustres 2000, Groman 2002); This variant is associated with the following publications: (PMID: 15241793, 16134171, 22020151, 14526128, 25087612, 9881185, 20717170, 20021716, 21184098, 26436105, 28603918, 20059485, 23951356, 12167682, 10923036, 33083013)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577642	SCV002141106	uncertain significance	Cystic fibrosis	2022-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 920 of the CFTR protein (p.Val920Met). This variant is present in population databases (rs373885282, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with cystic fibrosis, congenital absence of the vas deferens, and idiopathic pancreatitis (PMID: 10923036, 14526128, 23951356). ClinVar contains an entry for this variant (Variation ID: 53561). 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. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000731224	SCV002540902	uncertain significance	not provided	2021-09-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000577642	SCV002750305	uncertain significance	Cystic fibrosis	2024-02-14	criteria provided, single submitter	clinical testing	The p.V920M variant (also known as c.2758G>A), located in coding exon 17 of the CFTR gene, results from a G to A substitution at nucleotide position 2758. The valine at codon 920 is replaced by methionine, an amino acid with highly similar properties. This variant was reported in multiple individuals with CFTR-related disorders, including recurrent pancreatitis, congenital bilateral absence of the vas deferens, and disseminated bronchiectasis; however, complete genotype information was not provided (Bernardino AL et al. JOP, 2003 Sep;4:169-77; Amato F et al. J Mol Diagn, 2012 Jan;14:81-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577642	SCV000679006	not provided	Cystic fibrosis		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004537227	SCV004108847	uncertain significance	CFTR-related disorder	2024-04-03	no assertion criteria provided	clinical testing	The CFTR c.2758G>A variant is predicted to result in the amino acid substitution p.Val920Met. This variant was observed in the compound heterozygous state with p.F508del in a patient with congenital absence of the vas deferens and another patient with non-classic CF (Claustres et al. 2000. PubMed ID: 10923036). The c.2758G>A (p.Val920Met) variant has also been reported alongside a 5T/13TG allele (phase not specified) in a patient with a CFTR-related disorder (Trujillano et al. 2013. PubMed ID: 23687349 and Trujillano et al. 2015. PubMed ID: 26436105), in trans with a variant of uncertain significance in a patient with chronic pancreatitis (Cohn et al. 2005. PubMed ID: 16134171), and in affected individuals with other variants that potentially explain the phenotype (Groman et al. 2002. PubMed ID: 12167682; Masson et al. 2013. PubMed ID: 23951356). This variant is also reported in the heterozygous state without a second pathogenic variant in patients affected with CFTR-related disorders (Amato et al. 2012. PubMed ID: 22020151; René et al. 2011. PubMed ID: 20717170; de Becdelièvre et al. 2011. PubMed ID: 21184098) but was seen in the heterozygous state in a healthy control individual (Steiner et al. 2011. PubMed ID: 21520337). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.