Submissions for variant NM_000492.4(CFTR):c.1373del (p.Gly458fs)

dbSNP: rs397508196

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000046285	SCV000924259	pathogenic	Cystic fibrosis	2017-12-08	reviewed by expert panel	research
Counsyl	RCV000046285	SCV000486665	likely pathogenic	Cystic fibrosis	2016-07-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001004448	SCV001163493	pathogenic	Cystic fibrosis; Congenital bilateral aplasia of vas deferens from CFTR mutation		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000046285	SCV001362618	pathogenic	Cystic fibrosis	2023-06-14	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.1373delG (p.Gly458AspfsX11) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.1e-06 in 244091 control chromosomes, predominantly at a frequency of 6.5e-05 within the African or African-American subpopulation in the gnomAD database. c.1373delG has been reported in the literature in an African American individual affected with Cystic Fibrosis (example, Macek_1997). The following publications have been ascertained in the context of this evaluation (PMID: 9150159, 16049310). Multiple clinical diagnostic laboratories and the CFTR2 database have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000046285	SCV003002569	pathogenic	Cystic fibrosis	2022-04-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 53237). This variant is also known as 1504delG. This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 9150159). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Gly458Aspfs*11) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922).
Baylor Genetics	RCV003473451	SCV004213522	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-04-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000046285	SCV005559897	pathogenic	Cystic fibrosis	2024-07-21	criteria provided, single submitter	clinical testing	The c.1373delG pathogenic mutation, located in coding exon 10 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 1373, causing a translational frameshift with a predicted alternate stop codon (p.G458Dfs*11). This variant has been identified in conjunction with another CFTR variant in an individual who met clinical criteria for cystic fibrosis (McCravy MS et al. Eur Respir J, 2020 Jul;56:). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000046285	SCV000692321	pathogenic	Cystic fibrosis	2015-10-28	no assertion criteria provided	clinical testing