Submissions for variant NM_000138.5(FBN1):c.640G>A (p.Gly214Ser)

dbSNP: rs794728162

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000460503	SCV000544936	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-09-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 214 of the FBN1 protein (p.Gly214Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ectopia lentis, Marfan syndrome, aortopathy and thoracic aortic aneurysms and dissections (PMID: 15733436, 17657824, 22262941, 22772377, 26787436, 27611364). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199956). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586274	SCV000695580	pathogenic	Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections	2017-06-15	criteria provided, single submitter	clinical testing	Variant summary: The FBN1 c.640G>A (p.Gly214Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution in the first TB domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent from the large control database ExAC (0/121464 control chromosomes). The variant has been found to segregate with classical Marfan syndrome within a four-generation nonconsanguineous Chinese family (Dong_Mol Vis_2012). It has also been identified in patients with Marfan syndrome or Marfan-related disorders (Stheneur_EJHG_2009; Franken_Euro Heart J_2016). In addition, one clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf	RCV000766239	SCV000897653	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-11-20	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001269512	SCV001449550	pathogenic	not provided	2019-10-22	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000663867	SCV002025344	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS1, PP4
Ambry Genetics	RCV000766239	SCV002658896	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2018-12-29	criteria provided, single submitter	clinical testing	The p.G214S pathogenic mutation (also known as c.640G>A), located in coding exon 6 of the FBN1 gene, results from a G to A substitution at nucleotide position 640. The glycine at codon 214 is replaced by serine, an amino acid with similar properties. This mutation was initially described in a Chinese family with ectopia lentis and was reported to segregate with disease in affected family members (Sui RF et al. Zhonghua Yan Ke Za Zhi, 2004 Dec;40:828-31). Subsequently, this mutation has been described in multiple individuals with Marfan syndrome (MFS) from a variety of ethnic backgrounds, including one large family with segregation in 13 family members with MFS (Comeglio P et al. Hum. Mutat., 2007 Sep;28:928; Attanasio M et al. Clin. Genet., 2008 Jul;74:39-46; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8; Dong J et al. Mol. Vis., 2012 Jan;18:81-6; Franken R et al. Eur. Heart J., 2016 11;37:3285-3290). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000663867	SCV004034100	pathogenic	Marfan syndrome	2023-07-01	criteria provided, single submitter	research
Center for Medical Genetics Ghent, University of Ghent	RCV000663867	SCV000787227	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing