ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1365G>A (p.Ala455=) (rs79074685)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000245016 SCV000052123 likely benign not specified 2018-02-05 criteria provided, single submitter clinical testing Variant summary: CFTR c.1365G>A alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00044 in 225136 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00044 vs 0.013). The estimated prevalence of CF in Africans is 1/15000, and the estimated attributable risk of all non-common variants about 0.2, which makes the maximal allele frequency of all non-common pathogenic variants approximately 1:750 (Based on Rohlfs_CFTR_CC_2011). The variant was found in 37/7216 African chromosomes in ExAC (1:196) and 61/13678 in gnomAD (1/224), which is consistent with benign nature of the variant. c.1365G>A has been reported in the literature in individuals affected with Cystic Fibrosis. These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. In addition, the c.1365G>A variant has been found in two internal cases in homozygous condition. Both were presumably healthy women of reproductive age undergoing routine carrier screening. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory classified this variant as Likely benign and another lab classified it as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000245016 SCV000304469 likely benign not specified criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588680 SCV000696838 likely benign not provided 2016-04-25 criteria provided, single submitter clinical testing Variant summary: The c.1365G>A (p.Ala455Ala) variant affects a non-conserved nucleotide. 4/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect ESE site of SC35. However, these predictions are not validated by in vivo/vitro experimental studies yet. The variant of interest has been observed in one case with limited phenotypic information (Shrijver_2005). In addition, the c.1365G>A variant have been found in two internal cases in homozygous condition. Both were presumably healthy women of reproductive age undergoing routine carrier screening. The variant has been reported mainly in African controls:1. The prevalence of CF in Africans is 1/15000, and the attributable risk of all non-common variants about 0.2, which makes the maximal allele frequency of all non-common pathogenic variants approximately 1:750 (Based on Rohlfs_CC_2011). The variant was found in 37/7216 African chromosomes in ExAC (1:196), which is consistent with benign nature of the variant.2. The c.2988+1G>A and p.F508del variants are two most frequent pathogenic variants in Africans (up to 61% of all carriers, Rohlfs et al, 2011). The combined allele frequencies of these two variants in the African cohort from the ExAC database is 0.29% (30/10338). The p.Ala455Ala was found 37 times in 7216 African chromosomes in the same ExAC African cohort (0.51%). So the frequency of c.1365G>A alone is much higher than combined frequency of two most common pathogenic variants in the same cohort.Taken together, this variant is classified as likely benign.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000588680 SCV000700537 uncertain significance not provided 2017-10-11 criteria provided, single submitter clinical testing
Invitae RCV000588680 SCV001000713 benign not provided 2019-03-04 criteria provided, single submitter clinical testing

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