ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1265C>T (p.Ser422Phe) (rs201880593)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000429132 SCV000511495 benign not provided 2016-06-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001158657 SCV001320309 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000429132 SCV001552139 uncertain significance not provided no assertion criteria provided clinical testing The CFTR p.Ser422Phe variant was not identified in the Cosmic or MutDB databases but was identified in dbSNP (ID: rs201880593), ClinVar (reported benign by the Center for Pediatric Genomics Medicine at the Children's Mercy Hospital and Clinics), Clinvitae and LOVD 3.0. The variant was identified in control databases in 966 of 248446 chromosomes at a frequency of 0.003888 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: European (Finnish) in 230 of 19926 chromosomes (freq: 0.01154), African in 201 of 18444 chromosomes (freq: 0.0109), Other in 54 of 6140 chromosomes (freq: 0.008795), European (non-Finnish) in 418 of 112262 chromosomes (freq: 0.003723), Latino in 40 of 33502 chromosomes (freq: 0.001194), East Asian in 16 of 18542 chromosomes (freq: 0.000863) and Ashkenazi Jewish in 7 of 10004 chromosomes (freq: 0.0007), 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.Ser422 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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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