ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.3808G>A (p.Asp1270Asn) (rs11971167)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PharmGKB RCV000660771 SCV000783010 drug response ivacaftor response - Efficacy 2018-03-23 reviewed by expert panel curation PharmGKB Level of Evidence 1A: Annotation for a variant-drug combination in a CPIC or medical society-endorsed PGx guideline, or implemented at a PGRN site or in another major health system.
Invitae RCV000046985 SCV000074998 benign Cystic fibrosis 2019-12-31 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587433 SCV000228017 uncertain significance not provided 2018-05-11 criteria provided, single submitter clinical testing
GeneDx RCV000587433 SCV000568550 uncertain significance not provided 2017-12-05 criteria provided, single submitter clinical testing The D1270N variant in the CFTR gene has been reported previously in trans with the common delta F508 pathogenic variant in an individual with normal sweat chloride levels, a normal chest roentgenogram but who had CAVD (Anguiano et al., 1992). Expression studies in HeLa and FRT cells showed that D1270N transfected cells displayed decreased chloride transport activity compared to wild type cells (Fanen et al., 1999; Van Goor et al., 2014). However, D1270N has also been identified unaffected individuals who were compound heterozygous for D1270N and a definitively pathogenic variant (Sugarman et al., 2014). The D1270N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D1270N as a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587433 SCV000601108 uncertain significance not provided 2019-04-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000176372 SCV000602988 pathogenic Hereditary pancreatitis 2018-05-15 criteria provided, single submitter clinical testing The CFTR c.3808G>A, p.Asp1270Asn variant (rs11971167) has been reported in patients diagnosed with congenital bilateral absence of vas deferens (CBAVD), in trans with p.Phe508del (Anguiano 1992, Oates 1993), but is more commonly found in a complex allele (with p.Arg74Trp and p.Val201Met) in patients with CBAVD and pancreatitis (Bareil 2007, Casals 1995, Masson 2013, Steiner 2011). In individuals where the p.Asp1270Asn alone was reported in trans with p.Phe508del, they had normal or slightly elevated sweat chloride levels (Anguiano 1992, Padoa 1999). Functional characterization of the p.Asp1270Asn variant indicates reduced overall mRNA and protein expression (van Goor 2014), reduced chloride conductance (Sosnay 2013, van Goor 2014) and altered response patterns (Fanen 1999). However, protein maturation and glycosylation is comparable to wildtype (Fanen 1999, Sosnay 2013, van Goor 2014). This variant is found in the general population with an overall allele frequency of 0.1% (315/276666 alleles, including 3 homozygotes) in the Genome Aggregation Database. The aspartate at residue 1270 is highly conserved, and computational algorithms ( PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as very mildly pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000480239 SCV000696992 uncertain significance not specified 2020-07-23 criteria provided, single submitter clinical testing Variant summary: CFTR c.3808G>A (p.Asp1270Asn) results in a conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domain of the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0053 in 161806 control chromosomes (gnomAD v3 database and publications), including 5 homozygotes. This frequency is close to the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis phenotype (0.013). However, this variant is frequently reported in complex (i.e. in cis) with either the c.220C>T (p.Arg74Trp) and/or c.601G>A (p.Val201Met). The first two variants (i.e. R74W and D1270N) were individually found in control databases at very similar frequencies and allele counts (with the same number of homozygotes) in the African subpopulation. Therefore, although it is not possible to confirm that these variants occurred in the same individuals, it is very likely that the majority of the gnomAD (v3) population carried the [R74W;D1270N] complex allele. The variant has been reported in numerous patients with CF, CBAVD, lung cancer, idiopathic chronic pancreatitis, and recurrent respiratory infections without strong evidence for causality (e.g. Alonso_2007, Bombieri_1998, Masson_2013, Mercier_1995, Steiner_2011, Verlingue_1993) and it was determined to co-occur frequently on the same allele with R74W. The variant's complex forms, p.[R74W;D1270N] and p.[R74W;V201M;D1270N], are found in patients with CBAVD phenotype (e.g. Claustres_2000, Clausters_2004, Ratbi_2007, Steiner_2011, UMD database). The variant in its complex form did not cause CF in females when found in a compound heterozygous state with a disease-causing mutation (Claustres_2000, Verlingue_1993) and similarly, did not cause disease when reported as the single variant in trans with pathogenic mutations in male individuals (Terlizzi_2017). Functional studies showed that this variant was associated with mildly reduced cAMP-activated chloride conductance activity and a slight reduction in the synthesis of mature CFTR protein (Fanen_1999, Terlizzi_2017, Van Goor_2013). One publication states that clinical and functional data "indicate that such mutations are not enough to cause disease" when discussing the variant as a single allele or a complex allele with R74W (Terlizzi_2017). 10 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (5x), likely benign (3x), benign (1x) and very mildly pathogenic (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000046985 SCV000795824 uncertain significance Cystic fibrosis 2017-11-19 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000480239 SCV000967180 likely benign not specified 2018-07-18 criteria provided, single submitter clinical testing The p.Asp1270Asn variant in CFTR has been reported in isolation or as part of th e p.[Arg74Trp;Asp1270Asn] complex allele in several individuals with CFTR-relate d conditions (Aguiano 1992, Casals 1995, Fanen 1999, Padoa 1999, Ravnik-Glavac 2 000, Luzardo 2002, Girodon 2002, Masson 2013, Sosnay 2013, Terlizzi 2017, Behar 2017). However, it has also been identified in isolation in trans with known pat hogenic CFTR variants in 2 unaffected adult male individuals and as part of the p.[Arg74Trp;Asp1270Asn] allele in trans with a known pathogenic variant in 1 una ffected child (Terlizzi 2017). It has also been identified with the p.Val201Met allele as part of the p.[Arg74Trp;Val201Met;Asp1270Asn] complex allele in severa l individuals with CFTR-related conditions who carried additional pathogenic var iants in CFTR (Claustres 20004, Brugnon 2008, de Prada Merino 2010, Steiner 2011 , Masson 2013, Terlizzi 2017). However, the p.[Arg74Trp;Val201Met;Asp1270Asn] al lele has also been identified in trans with the p.Phe508del in twin boys who are reportedly unaffected, although the paper did not specify if they were examined for CBAVD (Brugnon 2008). In addition, the p.Asp1270Asn variant has been identi fied in 1.3% (315/24024) of African chromosomes, including 3 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). In sum mary, the p.Asp1270Asn variant in isolation or as part of the p.[Arg74Trp;Asp127 0Asn] complex allele is classified as likely benign based on the high allele fre quency and the presence of this variant in trans with known pathogenic variants in unaffected individuals, though the clinical significance of the p.[Arg74Trp;V al201Met;Asp1270Asn] complex allele is uncertain. ACMG/AMP Criteria applied: BS1 , BP2.
Mendelics RCV000046985 SCV001137497 likely benign Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001021198 SCV001182780 uncertain significance Inborn genetic diseases 2019-04-04 criteria provided, single submitter clinical testing Conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Illumina Clinical Services Laboratory,Illumina RCV001158873 SCV001320536 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Johns Hopkins Genomics,Johns Hopkins University RCV000046985 SCV001430641 likely pathogenic Cystic fibrosis 2020-06-11 criteria provided, single submitter clinical testing CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information.
OMIM RCV000007584 SCV000027785 pathogenic Congenital bilateral aplasia of vas deferens from CFTR mutation 1992-04-01 no assertion criteria provided literature only

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