ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.1408G>A (p.Val470Met) (rs213950)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036517 SCV000060172 benign not specified 2008-01-15 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000036517 SCV000110842 benign not specified 2017-09-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000036517 SCV000304471 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001095216 SCV000466513 likely benign CFTR-related disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Integrated Genetics/Laboratory Corporation of America RCV000036517 SCV000696842 benign not specified 2019-06-12 criteria provided, single submitter clinical testing Variant summary: CFTR c.1408G>A (p.Val470Met) results in a conservative amino acid change located in the ABC transporter-like domain (IPR003439) and AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.47 in 251166 control chromosomes in the gnomAD database, including 30261 homozygotes. The observed variant frequency is approximately 37 fold of the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Cystic Fibrosis phenotype (0.013), strongly suggesting that the variant is benign. Given the almost equal frequency of the G and A alleles at the c.1408 locus in the general population, this variant is presented in different databases and publications with either G as the major allele (i.e. c.1408G>A (V470M)) or A (i.e. c.1408A>G (M470V)). The variant locus is reported in the literature as a polymorphism that cannot be considered as a disease predisposing factor by itself but when in cis with other disease-causing variants could influence incidence and presentation of symptoms. CFTR2 database states that based on "clinical information obtained from these patients, laboratory experiments performed on this variant, and analysis of groups of healthy individuals that carry this variant, we conclude that this variant does not cause CF when combined with another CF-causing variant. Most individuals with this variant (combined with another CF-causing variant) will be healthy. A small number of individuals may develop mild symptoms or be diagnosed with a CFTR-related disorder (CFTR-RD; see FAQs), but symptoms are not expected to be severe enough to meet the definition of CF." Association of the V470 allele with the 5T allele has been noted in CBAVD and bronchiectasis or chronic pancreatitis patients; the T5-V470 haplotype showing higher disease association than the T5-M470 haplotype while the Q1352H mutation found in a V470 background showed the strongest disease association (de Meeus_1998, Lee_2003, Sun_2003). Another study documented that homozygous M470 along with other CFTR variants were frequently observed in bronchiectasis patients (Guan_2018) while exclusive association between F508del allele and M470 allele has been evidenced (Nefzi_2015). In further contradiction to these reports, the common polymorphisms M470V, T854T, and Q1463Q had no significant association with pancreatitis, either individually or combined in haplotypes, in contrast to a previous reports (LaRusch_2014). Co-occurrences in cis with other pathogenic variant(s) on the same allele have been reported (example, CFTR c.3889dupT, p.S1297FfsX5 ; CFTR del2,3 or 2184insA), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function demonstrated that M470 CFTR proteins matured more slowly, and that they had a 1.7-fold increased intrinsic chloride channel activity compared with V470 CFTR proteins, suggesting that the M470V locus might also play a role in the partial penetrance of T5 as a disease mutation (Cuppens_1998). Moreover, E217G and Q1352H mutations in the M470 background caused a 60-80% reduction in CFTR-dependent Cl- currents and HCO3- transport activities (Lee_2003). However, none of these studies report evidence supporting a penetrant role for this specific variant in the pathophysiology of CF, CFTR-RD or any associated symptoms in an inherited context. Three ClinVar submitters (evaluation after 2014) cite the variant as benign (n=2) and once as likely benign. Based on the evidence outlined above, due to insufficient evidence demonstrating a highly penetrant association of this variant with CF and associated sub-phenotypes such as CBAVD, CFTR-RD in an inherited context, the variant was classified as benign.
GeneDx RCV000036517 SCV000714549 benign not specified 2017-12-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000007550 SCV001000411 benign Cystic fibrosis 2019-12-31 criteria provided, single submitter clinical testing
CFTR-France RCV000007550 SCV001169205 benign Cystic fibrosis 2018-01-29 criteria provided, single submitter curation the variant does not result in CFTR-RD neither
Ambry Genetics RCV001011421 SCV001171742 benign Inborn genetic diseases 2015-03-17 criteria provided, single submitter clinical testing
OMIM RCV000007550 SCV000027751 benign Cystic fibrosis 1990-11-01 no assertion criteria provided literature only
Genetic Services Laboratory,University of Chicago RCV000036517 SCV000150654 likely benign not specified no assertion criteria provided clinical testing Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

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