Submissions for variant NM_000138.5(FBN1):c.7708G>A (p.Glu2570Lys)

dbSNP: rs886038786

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002310834	SCV000317723	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-02-09	criteria provided, single submitter	clinical testing	The p.E2570K pathogenic mutation (also known as c.7708G>A), located in coding exon 62 of the FBN1 gene, results from a G to A substitution at nucleotide position 7708. The glutamic acid at codon 2570 is replaced by lysine, an amino acid with similar properties, and is located in the calcium binding consensus sequence of the cbEGF like domain #41. This mutation has been reported in several individuals with Marfan syndrome (MFS) or clinical presentations consistent with MFS (Arbustini E et al. Hum. Mutat., 2005 Nov;26:494; Attanasio M et al. Clin. Genet., 2008 Jul;74:39-46; Baudhuin LM et al. J Hum Genet. 2015 May;60(5):241-52; Gentilini D et al. PLoS One. 2019 Sep;14(9):e0222506), and segregated with disease in three individuals in one family (Söylen B et al. Clin. Genet., 2009 Mar;75:265-70). In addition, this alteration has also been detected in aortic aneurysm and/or dissection cohorts (Tan L et al. Hum. Mol. Genet., 2017 Dec;26:4814-4822; Li Z et al. Sci China Life Sci. 2018 12;61(12):1545-1553; Overwater E et al. Hum Mutat. 2018 09;39(9):1173-1192). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000480933	SCV000568639	likely pathogenic	not provided	2023-03-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19159394, 16222657, 18435798, 28973303, 30341550, 29907982, 25652356, 31536524)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780252	SCV000917362	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7708G>A (p.Glu2570Lys) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250706 control chromosomes (gnomAD, Arbustini_2005, Attanasio_2008). c.7708G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome (e.g., Arbustini_2005, Attanasio_2008, Soylen_2009, Attanasio_2013, Overwater_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16222657, 18435798, 23684891, 29907982, 19159394). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000794952	SCV000934390	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-12-29	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 263398). This missense change has been observed in individuals with Marfan syndrome and Marfan syndrome or thoracic aortic aneurysm and dissection (PMID: 16222657, 18435798, 19159394, 28973303). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2570 of the FBN1 protein (p.Glu2570Lys).