Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000181509 | SCV000233812 | likely pathogenic | not provided | 2017-05-23 | criteria provided, single submitter | clinical testing | The N1382K likely pathogenic variant in the FBN1 gene has been reported in association in one of 262 unrelated individuals with Marfan syndrome or Marfan-like phenotype tested at a national health service laboratory; however, no detailed clinical information or segregation data were provided (Howarth et al., 2007). Additionally, the N1382K protein substitution caused by a different nucleotide substitution (c.4146 T>G) has been identified in an unrelated individual referred for TAAD / Marfan Syndrome / Related Disorders genetic testing at GeneDx. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N1382K 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 calcium-binding residue that is conserved across species, within the calcium-binding EGF-like 23 domain. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000181509 | SCV000695534 | uncertain significance | not provided | 2016-12-14 | criteria provided, single submitter | clinical testing | Variant summary: The FBN1 c.4146T>A (p.Asn1382Lys) is located in calcium binding EGF-like domain 18 of the protein and 4/4 in silico tools predict a damaging outcome for this variant. This variant is absent in 121088 control chromosomes from ExAC. In literature, this variant is reported as a 'mutation' found in one patient with Marfan or Marfan-like syndrome (Howarth_2007). Mutations at the same residue, N1382I and N1382S have also been reported in association with MFS (PMIDs 7611299 and 18087243), suggesting that the codon is mutational hot-spot. In addition, mutations in nearby residues (C1374G, C1374S, C1374Y, C1380Y, K1381N, M1384L, Y1387C, C1389R, C1391F, etc.) have been reported in association with Marfan syndrome or other FBN1-related disorder (HGMD), further supporting the functional importance of this region of the protein. One clinical laboratory in ClinVar has classified this variant as pathogenic and reports the variant in TAAD panel. Taken together, this variant is currently classified as VUS-possibly pathogenic. |