Submissions for variant NM_000492.4(CFTR):c.137C>T (p.Ala46Val)

gnomAD frequency: 0.00009  dbSNP: rs151020603

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000728272	SCV000855825	uncertain significance	not provided	2018-09-04	criteria provided, single submitter	clinical testing
Mendelics	RCV000757789	SCV000886163	uncertain significance	Cystic fibrosis	2023-12-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780112	SCV000917156	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.137C>T (p.Ala46Val) results in a non-conservative amino acid change in 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 3.2e-05 in 250758 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.137C>T has been reported in the literature as a non-informative genotype (second allele not specified) in at-least one individual reportedly affected with Cystic Fibrosis (example, daSilvaFilho_2021). These report(s) do 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. The following publication has been ascertained in the context of this evaluation (PMID: 32819855). A different variant located at the same codon (c.137C>A, p.Ala46Asp) has been classified as pathogenic, however, current evidence is insufficient to determine the effect of p.Ala46Val on protein function. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000757789	SCV000944038	uncertain significance	Cystic fibrosis	2022-08-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 46 of the CFTR protein (p.Ala46Val). This variant is present in population databases (rs151020603, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 593277). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000757789	SCV001167244	uncertain significance	Cystic fibrosis	2019-10-19	criteria provided, single submitter	clinical testing	CFTR c.137C>T has not been reported in the literature, to our knowledge. This CFTR variant (rs151020603) is rare (<0.1%) in a large population dataset1 (gnomAD: 12/282150 total alleles; 0.004%; no homozygotes). There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Three submitters classified it as a variant of uncertain clinical significance and one as likely pathogenic. Two bioinformatic tools queried predict that this substitution would be damaging, and the alanine residue at this position is highly evolutionarily conserved across all species assessed. This variant is located within the same residue as p.Ala46Asp, a previously reported alternate pathogenic missense variant. We consider the clinical significance of c.137C>T uncertain at this time.
Genome-Nilou Lab	RCV000757789	SCV001821979	uncertain significance	Cystic fibrosis	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001592932	SCV001821980	uncertain significance	Congenital bilateral aplasia of vas deferens from CFTR mutation	2021-07-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000728272	SCV002540881	uncertain significance	not provided	2021-06-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000757789	SCV002700966	uncertain significance	Cystic fibrosis	2020-09-02	criteria provided, single submitter	clinical testing	The p.A46V variant (also known as c.137C>T), located in coding exon 2 of the CFTR gene, results from a C to T substitution at nucleotide position 137. The alanine at codon 46 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000728272	SCV003799399	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing	The CFTR c.137C>T; p.Ala46Val variant (rs151020603), to our knowledge, is not reported in the medical literature but is reported in the SickKids CFTR database in an individual with a positive newborn screen (see link). This variant is reported in ClinVar (Variation ID: 593277) and is found in the African population with an allele frequency of 0.05% (12/24960 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (c.137C>A, p.Ala46Asp) have been reported in individuals with cystic fibrosis and is considered pathogenic (Tzetis 1995, Van Goor 2014). The alanine at codon 46 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.468). However, given the lack of clinical and functional data, the significance of the p.Ala46Val variant is uncertain at this time. References: SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/Home.html Tzetis M et al. Identification of two novel mutations (296 + 1G-C and A46D) in exon 2 of the CFTR gene in Greek cystic fibrosis patients. Mol Cell Probes. 1995 Aug;9(4):283-5. PMID: 7477025. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36.PMID: 23891399.
Natera, Inc.	RCV000757789	SCV001464070	uncertain significance	Cystic fibrosis	2020-09-16	no assertion criteria provided	clinical testing