Submissions for variant NM_000138.5(FBN1):c.6890C>T (p.Thr2297Met)

gnomAD frequency: 0.00003  dbSNP: rs773785908

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780259	SCV000917369	uncertain significance	not specified	2024-02-27	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.6890C>T (p.Thr2297Met) results in a non-conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251282 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6890C>T has been reported in the literature in affected individuals undergoing testing for Thoracic Aortic Aneurisms or Marfan Syndrome (example, Landis_2017, Somers_2016). 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: 27112580, 28550590). ClinVar contains an entry for this variant (Variation ID: 632817). Based on the evidence outlined above, the variant was classified as uncertain significance.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000851302	SCV000993592	uncertain significance	Marfan syndrome	2018-08-30	criteria provided, single submitter	research
Invitae	RCV001062885	SCV001227709	likely pathogenic	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2297 of the FBN1 protein (p.Thr2297Met). This variant is present in population databases (rs773785908, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of Marfan syndrome and/or clinical features of thoracic aortic aneurysm (PMID: 27112580; Invitae). ClinVar contains an entry for this variant (Variation ID: 632817). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. This variant disrupts the p.Thr2297 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Illumina Laboratory Services, Illumina	RCV000851302	SCV001275271	uncertain significance	Marfan syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001117110	SCV001275272	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001117111	SCV001275273	uncertain significance	Weill-Marchesani syndrome	2018-01-15	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001117112	SCV001275274	uncertain significance	Acromicric dysplasia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001118750	SCV001277057	uncertain significance	Stiff skin syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001118751	SCV001277058	uncertain significance	Ectopia lentis 1, isolated, autosomal dominant	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001117110	SCV001332870	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2017-12-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001117110	SCV001351276	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-08-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 2297 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 affected with Marfan syndrome (PMID: 27112580, 28550590). This variant has been identified in 8/282666 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.
GeneDx	RCV002272352	SCV002558297	uncertain significance	not provided	2022-07-25	criteria provided, single submitter	clinical testing	Identified in patients with Marfan syndrome (Somers et al., 2016) and thoracic aortic aneurysm (TAA) (Landis et al., 2017) in published literature; Although located in a calcium-binding EGF-like domain of the FBN1 gene, it does not affect a cysteine residue within this domain; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28550590, 27112580)
Fulgent Genetics, Fulgent Genetics	RCV002507349	SCV002815227	uncertain significance	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	2022-04-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000851302	SCV004822418	uncertain significance	Marfan syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 2297 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 affected with Marfan syndrome (PMID: 27112580, 28550590). This variant has been identified in 8/282666 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	RCV001117110	SCV005032478	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-03-06	criteria provided, single submitter	clinical testing	The p.T2297M variant (also known as c.6890C>T), located in coding exon 56 of the FBN1 gene, results from a C to T substitution at nucleotide position 6890. The threonine at codon 2297 is replaced by methionine, an amino acid with similar properties. This variant has been reported in an individual in a Marfan syndrome cohort but clinical details were limited (Somers AE et al. Am J Med Genet A, 2016 Jul;170:1786-90). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.