ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.4270C>G (p.Pro1424Ala) (rs201273753)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000242618 SCV000317386 uncertain significance Cardiovascular phenotype 2017-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000035194 SCV000190205 uncertain significance Marfan syndrome 2014-06-01 no assertion criteria provided research
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000035194 SCV000678218 uncertain significance Marfan syndrome 2017-08-01 criteria provided, single submitter clinical testing FBN1 NM_000138.4 exon35 p.Pro1424Ala (c.4270C>G): This variant has been reported in the literature in at least 9 individuals with a clinical suspicion or diagnosis of Marfan syndrome, two of whom reported as compound heterozygotes (Collod-Beroud 1998 PMID:9399842, Comeglio 2001 PMID:11748851, Biggin 2004 PMID:14695540, Comeglio 2007 PMID:17657824, Howarth 2007 PMID:17627385, Stheneur 2009 PMID:19293843, Turner 2009 PMID:19161152, Callier 2013 PMID:23506379, Arnaud 2017 PMID:27582083). This variant is present in 29/126658 European individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs201273753). This variant is present in ClinVar (Variation ID:42355). Evolutionary conservation and computational predictive tools for this variant are unclear. Of note, the frequency of this variant is inconsistent with the expected incidence of this condition and several entries in ClinVar have noted this information in their classification. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Center for Medical Genetics Ghent,University of Ghent RCV000035194 SCV000787041 uncertain significance Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing
Color RCV000771903 SCV000904667 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-06-05 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the calcium-binding EGF-like motif 24 of the FBN1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals affected with Marfan syndrome or other FBN1-related conditions (PMID: 9399842, 11748851, 14695540, 17657824, 17627385, 19293843, 23506379, 25812041). This variant has been found in an individual with isolated aortic aneurysms but the variant did not segregate with the phenotype in the family (PMID: 26621581). This variant has also been identified in 54/277166 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to the lack of functional studies, occurrence in the general population and limited segregation analysis in affected families, available evidence is insufficient to determine the pathogenicity of this variant conclusively.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000586163 SCV000702389 uncertain significance not provided 2016-10-20 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765222 SCV000896458 uncertain significance Ectopia lentis, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2; Acromicric dysplasia; Geleophysic dysplasia 2; Marfan lipodystrophy syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000586163 SCV000233818 uncertain significance not provided 2018-03-29 criteria provided, single submitter clinical testing The P1424A variant of uncertain significance in the FBN1 gene has previously been reported in association with Marfan syndrome or other FBN1-related disorders (Collod-Beroud et al., 1998; Comeglio et al., 2001; Biggin et al., 2004; Howarth et al., 2007; Turner et al., 2009; Callier et al., 2013; Regalado et al., 2015; Wooderchak-Donahue et al., 2015; Arnaud et al., 2017). Additionally, this variant did not segregate with aortic disease in one family with familial TAAD (Regalado et al., 2015), and it did not segregate with ectopia lentis in the affected son of an individual with Marfan syndrome, who also harbored a second variant in the FBN1 gene which did segregate in the affected son (Arnaud et al., 2017). Moreover, the P1424A variant is observed in 6/11576 (0.05%) alleles from individuals of Latino ancestry and in 15/66728 (0.02%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P1424A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs within a calcium-binding EGF-like domain at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Likely pathogenic missense variants in nearby residues (C1420F, C1420R, C1420Y, C1420W, N1422S) in the FBN1 gene have been reported at GeneDx and/or reported in the Human Gene Mutation Database in association with FBN1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Nevertheless, P1424A does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Beroud et al., 2003). Furthermore, while a missense variant at the same residue (P1424S) has also been previously reported in association with Marfan syndrome (Arbustini et al., 2005), its clinical significance remains to be definitively determined.
Integrated Genetics/Laboratory Corporation of America RCV000586163 SCV000695537 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing Variant summary: The FBN1 c.4270C>G (p.Pro1424Ala) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 22/121498 control chromosomes at a frequency of 0.0001811, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125). The variant has been reported in the literature in multiple affected individuals including 6 individuals with MFS (Comeglio_2001, Turner_2009, Wooderchak-Donahue_2015, Franken_2016), 2 individuals with incomplete MFS (Collod-Beroud_1998, Biggin_2004), 1 individual with FTAAD, although the variant of interest did not segregate with aortic disease in the family (Regalado_2016), 2 individuals with Shprintzen-Goldberg syndrome (Stheneur_2009) and 2 individuals with marfanoid symptoms plus intellectual disability (Callier_2013). However, majority papers did not include any information on co-occurrence and co-segregation. A second variant at the same position (c.4270C>T, p.Pro1424Ser) has also been observed in individuals with clinical features of MFS (Arbustini_2005). Various publications and databases/clinical laboratories have classified the variant of interest from pathogenic to uncertain significance. Therefore, taking all the available information into consideration, due to the conflicting nature of this variant, it is classified as a VUS, until additional information becomes available.
Invitae RCV000226865 SCV000283627 uncertain significance Marfan syndrome; Thoracic aortic aneurysm and aortic dissection 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 1424 of the FBN1 protein (p.Pro1424Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs201273753, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in several individuals affected with Marfan syndrome (PMID: 9399842, 11748851, 14695540, 17657824, 17627385, 19293843, 23506379, 25812041, 25944730). This variant has been observed in an individual with Marfan syndrome (PMID: 27582083) in whom a pathogenic allele was also identified in FBN1, which suggests that this c.4270C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 42355). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000161118 SCV000058836 uncertain significance not specified 2013-10-21 criteria provided, single submitter clinical testing The Pro1424Ala missense variant in the FBN1 gene has previously been identified in at least two individuals with clinical features of Marfan syndrome (Collod-Be roud 1998, Comeglio 2001, Biggin 2004). Furthermore, a different variant at this position (Pro1424Ser) has also been reported in one other individual with clini cal features of Marfan syndrome (Arbustini, 2005). However, the Pro1424Ala varia nt was also detected in 0.05% (4/8592) European American chromosomes from a broa d population screened by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu; dbSNP rs201273753). Computational analyses (biochemical amino acid pr operties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong su pport for or against an impact to the protein. While the Pro1424Ala variant has been seen in several individuals with clinical features of Marfan syndrome, it h as also been seen at a low frequency in the general population. In summary, addi tional information is needed to assess the clinical significance of this variant .
University of Washington Center for Mendelian Genomics,University of Washington RCV000755199 SCV000883028 uncertain significance Familial thoracic aortic aneurysm; Acute aortic dissection 2016-01-20 no assertion criteria provided research

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