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

dbSNP: rs201880593

Total submissions: 6

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 Laboratory Services, Illumina	RCV001158657	SCV001320309	uncertain significance	CFTR-related disorder	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.
Genome-Nilou Lab	RCV001588894	SCV001822044	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001588894	SCV002681411	uncertain significance	Cystic fibrosis	2022-03-23	criteria provided, single submitter	clinical testing	The p.S422F variant (also known as c.1265C>T), located in coding exon 10 of the CFTR gene, results from a C to T substitution at nucleotide position 1265. The serine at codon 422 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was detected in an individual with cystic fibrosis or a CFTR-related disorder; however, complete genotype and phenotype information was not provided (Trujillano D et al. Mol Genet Genomic Med, 2015 Sep;3:396-403). This variant was previously reported in the SNPDatabase as rs201880593. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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.
Natera, Inc.	RCV001158657	SCV002080572	likely benign	CFTR-related disorder	2021-02-26	no assertion criteria provided	clinical testing