ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000245016 SCV000304469 likely benign not specified criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 RCV001085484 SCV001000713 benign Cystic fibrosis 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV001011059 SCV001171338 likely benign Inborn genetic diseases 2014-12-19 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Clinical Services Laboratory,Illumina RCV001161865 SCV001323776 likely benign CFTR-related disorders 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Nilou-Genome Lab RCV001588827 SCV001822050 likely pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 2021-07-22 criteria provided, single submitter clinical testing

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