Submissions for variant NM_000138.5(FBN1):c.5443G>A (p.Gly1815Ser)

gnomAD frequency: 0.00002  dbSNP: rs745680336

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV003105811	SCV003762193	uncertain significance	Marfan syndrome	2022-12-01	reviewed by expert panel	curation	NM_00138 c.5443G>A is a missense variant in FBN1 predicted to cause a substitution of a Glycine by Serine at amino acid 1815 (p.Gly1815Ser). This variant has been reported 3 times in ClinVar: once as likely pathogenic and twice as a variant of uncertain significance (Variation ID: 200064). This variant has been reported in the literature in 2 probands. It was identified in the homozygous state in an individual with autism spectrum disorder, global developmental delays, arachnodactyly, and dysmorphic features (PMID: 32655337); of note, homozygous variants of uncertain significance were identified in two other genes in this individual, and all 3 homozygous variants were found to segregate with disease in a similarly affected sibling. It was identified in another individual with sudden unexplained death in epilepsy, for which an autopsy did not identify any cardiac abnormalities (PMID: 27930701). This variant was also identified in an internal proband with thoracic aortic dissection and a systemic score >7 however, a pathogenic nonsense variant in FBN1 was also identified in this individual (BP2) and was considered to explain the phenotype . This variant has been identified in 0.0033% of individuals of South Asian origin in gnomAD v2.1.1. (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein. The constraint z-score for missense variants affecting FBN1 is 5.06 however due to the presence of one benign argument PP2 cannot be used . In summary, this variant meets the criteria to be classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BP2
GeneDx	RCV000181544	SCV000233847	likely pathogenic	not provided	2013-02-06	criteria provided, single submitter	clinical testing	p.Gly1815Ser (GGC>AGC): c.5443 G>A in exon 45 of the FBN1 gene (NM_000138.4)The Gly1815Ser variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gly1815Ser results in a non-conservative amino acid substitution of a non-polar Glycine with a polar Serine at a position that is conserved across species. In silico analysis predicts Gly1815Ser is damaging to the protein structure/function. Mutations in nearby residues (Glu1811Lys, Cys1812Arg, Cys1812Tyr, Cys1818Gly, Cys1818Tyr) have been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Furthermore, the Gly1815Ser variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, while Gly1815Ser is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant.The variant is found in TAAD panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702613	SCV000831473	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001176350	SCV001340314	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1815 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual showing clinical features resembling Marfan syndrome (Cortini et al., 2020, DOI: 10.4103/ds.ds_16_19). This variant has been observed in homozygosity in two siblings affected with autism spectrum disorder, arachnodactyly and facial features consistent with Marfan syndrome but not affected with cardiovascular problems (PMID: 32655337). This variant has been identified in 4/251202 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001176350	SCV002653000	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-06-02	criteria provided, single submitter	clinical testing	The p.G1815S variant (also known as c.5443G>A), located in coding exon 44 of the FBN1 gene, results from a G to A substitution at nucleotide position 5443. The glycine at codon 1815 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a sudden unexplained death cohort and in an individual who had some overlapping features with Marfan syndrome (Sanchez O et al. PLoS One, 2016 Dec;11:e0167358; Cortini F, et al. Dermatol Sin, 2020;38:98-101). This variant was also described as a homozygote in two siblings with autism, arachnodactyly and skeletal problems from a consanguineous mating. The parents were reported to be heterozygous for this alteration and absent of features of Marfan syndrome (Farajzadeh Valilou S et al. Mol Syndromol, 2020 Jun;11:62-72). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003105811	SCV004814657	uncertain significance	Marfan syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1815 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual showing clinical features resembling Marfan syndrome (Cortini et al., 2020, DOI: 10.4103/ds.ds_16_19). This variant has been observed in homozygosity in two siblings affected with autism spectrum disorder, arachnodactyly and facial features consistent with Marfan syndrome but not affected with cardiovascular problems (PMID: 32655337). This variant has been identified in 4/251202 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700547	SCV005203809	uncertain significance	not specified	2024-07-02	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.5443G>A (p.Gly1815Ser) results in a non-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 allele was found at a frequency of 1.6e-05 in 251202 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5443G>A has been reported in the literature in individuals affected with sudden unexplained death (Sanchez_2016) or autism spectrum disorder with skeletal abnormalities (Farajzadeh Valilou_2020). These reports do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32655337, 27930701). ClinVar contains an entry for this variant (Variation ID: 200064). Based on the evidence outlined above, the variant was classified as uncertain significance.