ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.2758G>A (p.Val920Met) (rs373885282)

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Total submissions: 9
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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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000731224 SCV000859011 uncertain significance not provided 2018-01-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282470 SCV000885175 uncertain significance none provided 2019-10-04 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 (SIFT, PolyPhen-2) predict that this variant is deleterious. 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. Bernardino AL et al. CFTR, PRSS1 and SPINK1 mutations in the development of pancreatitis in Brazilian patients. JOP. 2003 Sep;4(5):169-77. 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. Cohn JA et al. Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. Hum Mutat. 2005 Oct;26(4):303-7. 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. 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. 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. 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.
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 2020-10-01 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 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (0.00014 vs 0.013), allowing no conclusion about variant significance. In a conservative assessment, c.2758G>A has been reported in the literature in individuals affected with Non-Classic Cystic Fibrosis, such as, in trans with p.F508del in CBAVD (n=1), CF (n=1) (Claustres_2000), with p.F508del and the 5T allele, phase non specified in non-classic CF (n=1) (Groman_2002), in trans with another VUS in sporadic ICP (n=1) (Cohn_2005), heterozygous in a healthy control individual (Steiner_2011), with another CTRC gene variant (p.Ala73Thr) of unknown pathogenicity in an individual with non specified ICP (Mason_2013), a case of hyperechogenic fetal bowel with a non-informative genotype (Rene_2011 and deBecdelievre_2011), as an isolated variant in two patients with CFTR-RD (Amato_2012), and with CFTR 5T-TG(13) allele, phase not specified in another patient with CFTR-RD (Trujillano_2013 and Trujillano_2015). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4, likely pathogenic, n=1). 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
Nilou-Genome Lab RCV000577642 SCV001822121 uncertain significance Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577642 SCV000679006 not provided Cystic fibrosis no assertion provided literature only

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