Submissions for variant NM_000138.5(FBN1):c.6388G>A (p.Glu2130Lys)

dbSNP: rs794728334

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181698	SCV000234001	likely pathogenic	not provided	2022-06-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 200191; ClinVar); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17253931, 18435798, 19533785, 19293843, 17663468, 26684006, 31098894, 27234404, 20093880, 27382335, 27582083, 28098115, 30870686, 29845260, 32679894, 31825148)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000181698	SCV000603625	pathogenic	not provided	2017-08-20	criteria provided, single submitter	clinical testing	The FBN1 c.6388G>A, p.Glu2130Lys variant has been reported in multiple individuals diagnosed with Marfan syndrome (Tjeldhorn 2006, Rand-Hendriksen 2007, Attanasio 2008, Stheneur 2009). It is listed in the ClinVar database (Variation ID: 200191), in the dbSNP variant database (rs794728334), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Exome Aggregation Consortium). The glutamine at residue 2130 is highly conserved, lies in the cbEGF domain, and any variation in the conserved residues of the consensus sequence is considered pathogenic (Loeys 2010). Additionally, computational algorithms (Mutation Taster, PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Based on the above information, the variant is classified as pathogenic. References: Attanasio M et al. FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. Clin Genet. 2008 74(1):39-46. Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476-85. Rand-Hendriksen S et al. Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome. Am J Med Genet A. 2007 143A(17):1968-77. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 17(9):1121-8 Tjeldhorn L et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006 10(4):258-64.
Ambry Genetics	RCV001170531	SCV000738927	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2017-10-20	criteria provided, single submitter	clinical testing	The p.E2130K variant (also known as c.6388G>A), located in coding exon 52 of the FBN1 gene, results from a G to A substitution at nucleotide position 6388. The glutamic acid at codon 2130 is replaced by lysine, an amino acid with similar properties, and is located in the cbEGF-like #32 domain. This alteration has been reported in multiple individuals with Marfan syndrome and Marfan-like features, including at least one compound heterozygote (Tjeldhorn L et al. Genet. Test., 2006;10:258-64; Rand-Hendriksen S et al. Am. J. Med. Genet. A, 2007 Sep;143A:1968-77; Attanasio M et al. Clin. Genet., 2008 Jul;74:39-46; Chung BH et al. Am. J. Med. Genet. A, 2009 Jul;149A:1452-9; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8; Arnaud P et al. J. Med. Genet., 2017 Feb;54:100-103). In one Egyptian family, this alteration was also reported to segregate with clinical features in additional family members (Al-Haggar M et al. Saudi J Kidney Dis Transpl; 2017 Jan-Feb; 28:141-148). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659564	SCV000781398	pathogenic	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768213	SCV000898689	likely pathogenic	Ectopia lentis 1, isolated, autosomal dominant; Marfan syndrome; MASS syndrome; Stiff skin syndrome; Weill-Marchesani syndrome 2, dominant; Acromicric dysplasia; Geleophysic dysplasia 2; Progeroid and marfanoid aspect-lipodystrophy syndrome	2021-11-22	criteria provided, single submitter	clinical testing	FBN1 NM_000138.4 exon 53 p.Glu2130Lys (c.6388G>A): This variant has been reported in the literature in at least 5 individuals meeting Ghent criteria for Marfan syndrome (Tjeldhorn 2006 PMID:17253931, Rand-Hendriksen 2007 PMID:17663468, Attanasio 2008 PMID:18435798, Stheneur 2009 PMID:19293843, Al-Haggar 2017 PMID:28098115, Zhang 2018 PMID:29845260) and in one female with suspected Marfan syndrome who did not meet Ghent criteria (Chung 2009 PMID:19533785). This variant was also reported to segregate with disease in at least 3 affected family members (Al-Haggar 2017 PMID:28098115). This variant is not present in large control databases. It is present in ClinVar, with several labs classifying this variant as likely pathogenic or pathogenic (Variation ID:200191). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Invitae	RCV000824568	SCV000965470	pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-03-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 200191). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 17253931, 19293843, 19533785, 28098115; Invitae). 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 2130 of the FBN1 protein (p.Glu2130Lys).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170531	SCV001333115	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2020-02-19	criteria provided, single submitter	clinical testing
Centre of Medical Genetics, University of Antwerp	RCV000659564	SCV002025391	likely pathogenic	Marfan syndrome	2021-03-01	criteria provided, single submitter	research	PM2, PS6, PP4
3billion	RCV000659564	SCV002059182	pathogenic	Marfan syndrome	2022-01-03	criteria provided, single submitter	clinical testing	The variant was co-segregated with Marfan syndrome in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 28098115, 29845260, 17253931, PP1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 28098115, 18435798, 17663468, 17253931, 19533785, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.974, 3CNET: 0.981, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, University Hospital Muenster	RCV002287382	SCV002578063	pathogenic	Abnormality of connective tissue	2021-12-20	criteria provided, single submitter	clinical testing	ACMG categories: PS1,PM1,PM2,PP3,PP4
PreventionGenetics, part of Exact Sciences	RCV004528957	SCV004108242	pathogenic	FBN1-related disorder	2023-05-26	criteria provided, single submitter	clinical testing	The FBN1 c.6388G>A variant is predicted to result in the amino acid substitution p.Glu2130Lys. This variant was reported in numerous individuals with Marfan syndrome, including at least one case confirmed to have occurred de novo (Tjeldhorn et al. 2006. PubMed ID: 17253931; Table S1, Li et al. 2019. PubMed ID: 31098894; Vanem et al. 2020. PubMed ID: 31825148; Zhao et al. 2020. PubMed ID: 32209317; Supplementary Data, Stark et al. 2020. PubMed ID: 32679894). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Center for Medical Genetics Ghent, University of Ghent	RCV000659564	SCV000787225	likely pathogenic	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing