Validation of Pathogenicity of Gene Variants in Fanconi Anemia Using Patient-derived Dermal Fibroblasts

Park, Seon Young; Lee, Jong-Mi; Kim, Myung-Jin; Chung, Chun Kee; Lee, Jung Bok; Kim, Yonghwan; Kim, Myungshin

doi:10.3343/alm.2023.43.1.127

Cited by 1 publication

(2 citation statements)

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“…This variant substitutes cysteine for serine in the 25th cbEGF-like domain. Another amino-acid change (c.5330G > A, p.Cys1777Phe) was reported in a 35 classes are denoted as follows: DM, disease-causing mutation; DM?, likely pathogenic mutation reported to be disease-causing in the corresponding reports [23,[31][32][33], but where the author has indicated that there may be some degree of doubt, or subsequent evidence has come to light in the literature, calling the deleterious nature of the variant into question. † gnomAD subpopulation with the highest allele frequency except for Finnish, Ashkenazi Jewish, or "Other" populations.…”

Section: Discussionmentioning

confidence: 99%

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Re-evaluation of a Fibrillin-1 Gene Variant of Uncertain Significance Using the ClinGen Guidelines

Kim,

Kim

et al. 2023

Ann Lab Med

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Background: Marfan syndrome (MFS) is caused by fibrillin-1 gene (FBN1) variants. Mutational hotspots and/or well-established critical functional domains of FBN1 include cysteine residues, calcium-binding consensus sequences, and amino acids related to interdomain packaging. Previous guidelines for variant interpretation do not reflect the features of genes or related diseases. Using the Clinical Genome Resource (ClinGen) FBN1 variant curation expert panel (VCEP), we re-evaluated FBN1 germline variants reported as variants of uncertain significance (VUSs).Methods: We re-evaluated 26 VUSs in FBN1 reported in 161 patients with MFS. We checked the variants in the Human Genome Mutation Database, ClinVar, and VarSome databases and assessed their allele frequencies using the gnomAD database. Patients' clinical information was reviewed.Results: Four missense variants affecting cysteines (c.460T > C, c.1006T > C, c.5330G > C, and c.8020T > C) were reclassified as likely pathogenic and were assigned PM1_strong or PM1. Two intronic variants were reclassified as benign by granting BA1 (stand-alone). Four missense variants were reclassified as likely benign. BP5 criteria were applied in cases with an alternate molecular basis for disease, one of which (c.7231G > A) was discovered alongside a pathogenic de novo COL3A1 variant (c.1988G > T, p.Gly633Val).Conclusions: Considering the high penetrance of FBN1 variants and clinical variability of MFS, the detection of pathogenic variants is important. The ClinGen FBN1 VCEP encompasses mutational hotspots and/or well-established critical functional domains and adjusts the criteria specifically for MFS; therefore, it is beneficial not only for identifying pathogenic FBN1 variants but also for distinguishing these variants from those that cause other connective tissue disorders with overlapping clinical features.

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Section: Discussionmentioning

confidence: 99%

“…For instance, c.5608G > A, p.Gly1870Arg detected in case 13 may have been elevated to LPV by adding the co-segregation score PP1 if the identical variant had been confirmed in two tall brothers. Functional studies can help strengthen the evidence of pathogenicity in borderline cases [34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Re-evaluation of a Fibrillin-1 Gene Variant of Uncertain Significance Using the ClinGen Guidelines

Kim,

Kim

et al. 2023

Ann Lab Med

View full text Add to dashboard Cite

show abstract

Validation of Pathogenicity of Gene Variants in Fanconi Anemia Using Patient-derived Dermal Fibroblasts

Cited by 1 publication

References 8 publications

Re-evaluation of a Fibrillin-1 Gene Variant of Uncertain Significance Using the ClinGen Guidelines

Re-evaluation of a Fibrillin-1 Gene Variant of Uncertain Significance Using the ClinGen Guidelines

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