ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000731224 SCV000885175 likely pathogenic not provided 2018-02-02 criteria provided, single submitter clinical testing The CFTR c.2758G>A; p.Val920Met variant (rs373885282), is reported in trans with the pathogenic F508del variant in an individual with cystic fibrosis (CF), an individual with congenital bilateral absence of the vas deferens (CBAVD), and an individual with meconium ileus and pancreatic insufficiency (Claustres 2000, see SickKids link). The p.Val920Met/F508del genotype is also reported in a non-classic CF patient who also carries the 5T allele (Groman 2002). Furthermore, the p.Val920Met variant is reported as compound heterozygous with a pathogenic-mild CFTR variant in an individual with idiopathic chronic pancreatitis (ICP) (Cohn 2005), and in other individuals with ICP, CBAVD, or disseminated bronchiectasis with no additional CFTR variants identified or clarified (Amato 2012, Bernardino 2003). This variant is found in the general population with an overall allele frequency of 0.01% (36/277146 alleles, including 1 homozygote) in the Genome Aggregation Database. The valine at codon 920 is highly conserved and computational algorithms (SIFT, PolyPhen2) predict this variant to be deleterious. Based on available information, this variant is considered likely pathogenic but with varying clinical consequences. REFERENCES Link to SickKids 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.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577642 SCV000679006 not provided Cystic fibrosis no assertion provided literature only
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
Fulgent Genetics RCV000765926 SCV000897346 uncertain significance Bronchiectasis with or without elevated sweat chloride 1; Cystic fibrosis; Hereditary pancreatitis; Congenital bilateral absence of the vas deferens 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781291 SCV000919204 uncertain significance not specified 2017-11-28 criteria provided, single submitter clinical testing Variant summary: The CFTR c.2758G>A (p.Val920Met) variant involves the alteration of a conserved nucleotide, is predicted to be damaging by 4/5 in silico tools and is located in ABC transporter type 1, transmembrane domain (InterPro). This variant was found in 37/277858 control chromosomes (with 1 homozygote) at a frequency of 0.0001332 (in gnomAD and in publication controls), which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant was reported in several patients with CF, CBAVD and other CFTR-related disorders. The variant was found in compound heterozygous state with p.Phe508del (Claustres_2000) in two patients (one with CF and another with CBAVD), and with p.Phe508del and 5T allele in one non-classic CF patient (Groman_2002). Similarly, this variant is also found in compound heterozygous state with another pathogenic or unclassified variant or in heterozygous state in patients with idiopathic chronic pancreatitis, hyperechogenic fetal bowel, disseminated bronchiectasis and CFTRRD (e.g. Cohn_2005, Steiner_2011, Rene_2011, Amato_2012, Masson_2013, Trujillano_2013). In one chronic pancreatitis patient, another variant CTRC p.Ala73Thr that potentially explained the phenotype (in an assumed dominant inheritance) was also present (Masson_2013). These are no published functional studies for this variant. Taken together, this variant is classified as VUS-possibly pathogenic, until additional evidence becomes available.

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