ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.1312A>G (p.Thr438Ala) (rs201434579)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000436508 SCV000224843 uncertain significance not provided 2018-08-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000265349 SCV000466512 uncertain significance CFTR-related disorders 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000436508 SCV000510886 benign not provided 2016-06-07 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000436508 SCV001552749 uncertain significance not provided no assertion criteria provided clinical testing The CFTR p.Thr438Ala variant was not identified in the Cosmic or MutDB databases but was identified in dbSNP (ID: rs201434579), ClinVar (reported as a VUS by Emory and Illumina and benign by the Center for Pediatric Genomic Medicine at the Children's Mercy Hospital and Clinics), Clinvitae and LOVD 3.0. The variant was identified in control databases in 910 of 243424 chromosomes at a frequency of 0.003738 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 184 of 18116 chromosomes (freq: 0.01016), European (Finnish) in 195 of 20214 chromosomes (freq: 0.009647), Other in 46 of 6026 chromosomes (freq: 0.007634), European (non-Finnish) in 407 of 108932 chromosomes (freq: 0.003736), East Asian in 26 of 18052 chromosomes (freq: 0.00144), Latino in 42 of 33100 chromosomes (freq: 0.001269) and Ashkenazi Jewish in 10 of 9894 chromosomes (freq: 0.001011), but was not observed in the South Asian population. Trujillano et al. (2015) identified this variant in the heterozygous state in 1/177 cystic fibrosis patients but suggested the variant to be neutral (Trujillano_2015_PMID: 26436105). The p.Thr438 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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