ClinVar Miner

Submissions for variant NM_000492.3(CFTR):c.3672T>A (p.Asn1224Lys) (rs371475225)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000855591 SCV000696981 uncertain significance not specified 2019-02-06 criteria provided, single submitter clinical testing Variant summary: CFTR c.3672T>A (p.Asn1224Lys) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 244772 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (CF) (0.0015 vs. 0.013), allowing no conclusion about variant significance. However, it cannot be excluded that the variant may still represent a rare ethnic specific polymorphism. c.3672T>A has been reported in the literature in a 2 year old symptom-free individual with a pathogenic CFTR variant (F508del) in trans (Oca 2009), however, the clinical outcome of this case remains uncertain as it is unclear whether the variant may contribute to non-classic CF or CBAVD later. This report therefore does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000588038 SCV000885176 uncertain significance not provided 2018-02-06 criteria provided, single submitter clinical testing The CFTR c.3672T>A; p.Asn1224Lys variant (rs371475225) has been observed in trans with a common pathogenic CFTR variant (F508del) in an individual exhibiting no clinical signs of cystic fibrosis (Oca 2009). This variant is observed in the general population at an overall frequency of 0.02% (49/244772 alleles) in the Genome Aggregation Database. The asparagine at codon 1224 is weakly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be tolerated. However, given the lack of clinical and functional data, the significance of this variant cannot be determined with certainty. References: Oca F et al. Amniotic fluid digestive enzyme analysis is useful for identifying CFTR gene mutations of unclear significance. Clin Chem. 2009 Dec;55(12):2214-7.

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