Submissions for variant NM_000492.4(CFTR):c.413_415dup (p.Leu138dup)

dbSNP: rs397508686

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CFTR2	RCV000577362	SCV000924246	pathogenic	Cystic fibrosis	2018-08-31	reviewed by expert panel	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000577362	SCV001338283	pathogenic	Cystic fibrosis	2024-02-21	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.413_415dupTAC (p.Leu138dup) results in an in-frame duplication that is predicted to duplicate 1 amino acids into the encoded protein. The variant allele was found at a frequency of 4e-06 in 250744 control chromosomes. c.413_415dupTAC has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Behar_2017, Guo_2018, McGinniss_2005, Petrova_2019, Walkowiak_2001). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant confers residual function 1.6% of wild-type (Han_2018). The following publications have been ascertained in the context of this evaluation (PMID: 9272157, 11589722, 16189704, 28546993, 30046002, 30548586, 30558651).ClinVar contains an entry for this variant (Variation ID: 53905). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000577362	SCV001583173	pathogenic	Cystic fibrosis	2023-10-12	criteria provided, single submitter	clinical testing	This variant, c.413_415dup, results in the insertion of 1 amino acid(s) of the CFTR protein (p.Leu138dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs752803445, gnomAD 0.004%). This variant has been observed in individual(s) with CFTR-related conditions (PMID: 9272157, 16189704, 28546993, 30548586). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 546insCTA and c.411_412insCTA. ClinVar contains an entry for this variant (Variation ID: 53905). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CFTR function (PMID: 30046002). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509310	SCV001715936	pathogenic	not provided	2021-02-25	criteria provided, single submitter	clinical testing	PS3, PS4_Moderate, PM2, PM3, PM4, PP5
Institute of Human Genetics, University of Leipzig Medical Center	RCV000577362	SCV002574101	likely pathogenic	Cystic fibrosis	2022-09-05	criteria provided, single submitter	curation	This variant was identified in 4 unrelated patients 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_SUP, PM2_SUP, PM3_STR, PM4_SUP, PP4
Ambry Genetics	RCV000577362	SCV002628550	pathogenic	Cystic fibrosis	2024-04-08	criteria provided, single submitter	clinical testing	The c.413_415dupTAC pathogenic mutation (also known as p.L138dup), located in coding exon 4 of the CFTR gene, results from an in-frame duplication of TAC at nucleotide positions 413 to 415. This results in the duplication of an extra residue between codons 138 and 139. In our laboratory, this variant has been detected in trans with a pathogenic mutation in CFTR in an individual with intermediate sweat chloride levels (Ambry internal data). In an analysis of 40 CFTR mutations in Russian cystic fibrosis (CF) patients, this variant (reported as L138ins) was detected in 1.8% of the chromosomes (Adyan TA et al. Russ J Genet, 2018 Oct;54:1235-1244). This mutation was reported in a Polish male with congenital bilateral absence of the vas deferens (CBAVD) in conjunction with a 5T allele (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77). This alteration was also described in an individual with CF in conjunction with the c.3717+12191C>T mutation; however, the phase is unclear (Behar DM et al. Mol Genet Genomic Med, 2017 May;5:223-236). Based on internal structural analysis, this pathogenic variant is anticipated to result in a significant decrease in structural stability (Liu F et al. Cell, 2017 Mar;169:85-95.e8). In addition, human CF bronchial epithelial (CFBE) cells stably expressing this mutation (reported as L138ins) had only 1.6% of CFTR function, compared to cells expressing wild-type CFTR protein (Han ST et al. JCI Insight, 2018 Jul;3:). Furthermore, the duplication has an overall frequency of approximately 0.0004% (1/250744) in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	RCV000577362	SCV004814226	pathogenic	Cystic fibrosis	2019-10-29	criteria provided, single submitter	clinical testing	Criteria Codes: PM2 PM3_VStr PM4
Baylor Genetics	RCV004566881	SCV005057460	pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2023-12-28	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000577362	SCV000679461	not provided	Cystic fibrosis		no assertion provided	literature only
Natera, Inc.	RCV000577362	SCV001454015	pathogenic	Cystic fibrosis	2020-09-16	no assertion criteria provided	clinical testing