Submissions for variant NM_000492.4(CFTR):c.1860T>G (p.His620Gln)

dbSNP: rs397508315

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577374	SCV002174958	uncertain significance	Cystic fibrosis	2020-11-26	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 53407). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this variant affects CFTR protein function (PMID: 9736778, 9849891, 22722932, 11242048). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with glutamine at codon 620 of the CFTR protein (p.His620Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577374	SCV002573948	pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_MOD, PM3, PM2_SUP, PM5_STR, PP3, PP4
Ambry Genetics	RCV000577374	SCV002721906	likely pathogenic	Cystic fibrosis	2014-10-10	criteria provided, single submitter	clinical testing	The p.H620Q (also known as c.1860T>G) variant is located in exon 14 of the CFTR gene. This variant results from an T to G substitution at nucleotide position 1860. The histidine at codon 620 is replaced by glutamine, an amino acid with similar properties. This variant has been described in one individual with pancreatic insufficiency, recurrent pulmonary infections, and elevated sweat chloride, who was reported to be compound heterozygous for deltaF508 (Vankeerberghen et al. Hum. Mol. Genet. 1998 Oct;7(11):1761-9). Multiple in vitro studies have shown this variant, which is located in the regulatory domain of CFTR, results in a normally processed protein and increases chloride channel activity above that of the wild type protein (Vankeerberghen et al. Hum. Mol. Genet. 1998 Oct;7(11):1761-9l; Choi et al. Nature 2001 Mar;410(6824):94-7; Wei L et al. FEBS Lett. 1998 Nov 13;439(1-2):121-6). This variant has been detected in trans with a pathogenic mutation in CFTR in a set of twins by our laboratory. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. This amino acid position is highly conserved on sequence alignment of available vertebrate species. This variant is predicted to be probably damaging by PolyPhen and tolerated by SIFT in silico analyses. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577374	SCV000678971	not provided	Cystic fibrosis		no assertion provided	literature only