ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3409A>G (p.Met1137Val) (rs397508553)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000590826 SCV000696968 uncertain significance not provided 2017-06-28 criteria provided, single submitter clinical testing Variant summary: The CFTR c.3409A>G (p.Met1137Val) variant involves the alteration of a conserved nucleotide, resulting in a missense change in the ABC transporter type 1, transmembrane domain (InterPro). 3/4 in silico tools predict damaging outcome for this variant. This variant was found in the large control database ExAC and literature cohorts at a frequency of 0.0000163 (2/122962 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been identified in several individuals with nonclassic CF, neonatal hypertrypsinaemia, CBAVD, CFTR-related disorders and non-CF pulmonary phenotype (e.g., Trujillano_MGGM_2015; Lucarelli_MM_2015; El-Seedy_HM_2012; Green_RR_2010; Durno_Gastroenterology_2002; Bombieri_HumGenet_1998). The variant has been found to cause partially defective cAMP-induced chloride conduction in electrophysiological assays (Vankeerberghen_FEBS Letters_1998), though protein processing and glycosylation were not affected. Additionally, published reports suggest the allele may cause a milder CF phenotype when in compound heterozygosity with a known pathogenic mutation like deltaF508 (e.g., Castellani_JMG_2001; Lucarelli_MM_2015), which is in line with the experimental evidence that suggests the allele is not a functionally null. Another missense change at the same residue, p.Met1137Arg has also been described in association with CF including functional evidence that p.Met1137Arg most probably causes defect in maturation (Vankeerberghen_FEBS Letters_1998). One clinical diagnostic laboratory (via ClinVar) has identified this variant without providing a classification. Taken together, this variant is currently classified as VUS-possibly pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000577660 SCV000679376 not provided Cystic fibrosis no assertion provided literature only

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