Submissions for variant NM_000492.4(CFTR):c.4129G>C (p.Asp1377His)

dbSNP: rs150683293

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000300236	SCV000342707	uncertain significance	not provided	2016-06-23	criteria provided, single submitter	clinical testing
CFTR-France	RCV001009485	SCV001169580	pathogenic	CFTR-related disorder	2018-01-29	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852982	SCV002170632	pathogenic	Cystic fibrosis	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1377 of the CFTR protein (p.Asp1377His). This variant is present in population databases (rs150683293, gnomAD 0.0009%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 8556303, 9239681, 9272157). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53896). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488366	SCV004241757	uncertain significance	not specified	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.4129G>C (p.Asp1377His) results in a non-conservative amino acid change located in the ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251184 control chromosomes (gnomAD). c.4129G>C has been reported in the literature in individuals affected with Congenital Bilateral Absence Of The Vas Deferens (e.g. Costes_1995, DeBraekeleer_1996, Dork_1997, Steiner_2011). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8556303, 9239681, 9272157, 21520337, 34405919). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=2) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Ambry Genetics	RCV001852982	SCV005107487	uncertain significance	Cystic fibrosis	2024-04-10	criteria provided, single submitter	clinical testing	The p.D1377H variant (also known as c.4129G>C), located in coding exon 25 of the CFTR gene, results from a G to C substitution at nucleotide position 4129. The aspartic acid at codon 1377 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV000300236	SCV005409355	uncertain significance	not provided	2024-04-25	criteria provided, single submitter	clinical testing	PP3, PM2_moderate, PM3_supporting