Submissions for variant NM_000138.5(FBN1):c.4270C>G (p.Pro1424Ala)

gnomAD frequency: 0.00034  dbSNP: rs201273753

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000161118	SCV000058836	uncertain significance	not specified	2013-10-21	criteria provided, single submitter	clinical testing	The Pro1424Ala missense variant in the FBN1 gene has previously been identified in at least two individuals with clinical features of Marfan syndrome (Collod-Be roud 1998, Comeglio 2001, Biggin 2004). Furthermore, a different variant at this position (Pro1424Ser) has also been reported in one other individual with clini cal features of Marfan syndrome (Arbustini, 2005). However, the Pro1424Ala varia nt was also detected in 0.05% (4/8592) European American chromosomes from a broa d population screened by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu; dbSNP rs201273753). Computational analyses (biochemical amino acid pr operties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong su pport for or against an impact to the protein. While the Pro1424Ala variant has been seen in several individuals with clinical features of Marfan syndrome, it h as also been seen at a low frequency in the general population. In summary, addi tional information is needed to assess the clinical significance of this variant .
GeneDx	RCV000586163	SCV000233818	uncertain significance	not provided	2022-12-21	criteria provided, single submitter	clinical testing	Reported in an unaffected relative in the published literature and observed in unaffected relatives referred for testing at GeneDx (Howarth et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); This variant is associated with the following publications: (PMID: 9399842, 25812041, 25637381, 28655553, 14695540, 19161152, 19293843, 11748851, 23506379, 24941995, 26621581, 25944730, 27647783, 27582083, 17627385, 27153395, 31098894, 12938084, 17657824, 31211626, 27535533)
Invitae	RCV000226865	SCV000283627	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000771903	SCV000317386	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-05-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000035194	SCV000678218	benign	Marfan syndrome	2022-03-07	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in several individuals with a clinical suspicion or diagnosis of Marfan syndrome (Selected publications: Comeglio 2001 PMID: 11748851, Comeglio 2007 PMID: 17657824, Stheneur 2009 PMID: 19293843, Arnaud 2017 PMID: 27582083). This variant is present in gnomAD (Highest reported MAF: 0.2% [31/15280]; https://gnomad.broadinstitute.org/variant/15-48472617-G-C?dataset=gnomad_r3) and in ClinVar (Variation ID:42355). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, a different variant at the same amino acid position (p.Pro1424Ser) has been previously reported in association with disease (Arbustini 2005 PMID: 16222657; Piqueras-Flores 2019 PMID: 31053375). However, because of this variant's high frequency in the general population, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000161118	SCV000695537	likely benign	not specified	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.4270C>G (p.Pro1424Ala) 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 0.0002 in 251532 control chromosomes. The observed variant frequency is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is benign. c.4270C>G has been reported in the literature in individuals affected with features of or undergoing testing for Marfan Syndrome/familial thoracic aortic aneurysms and dissections. These data do not allow any conclusion about variant significance. 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: 11748851, 14695540, 12938084, 17657824, 17627385, 19161152, 9399842, 19293843, 23506379, 24941995, 25637381, 27153395, 26787436). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=11, B/LB, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Eurofins Ntd Llc (ga)	RCV000586163	SCV000702389	uncertain significance	not provided	2016-10-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765222	SCV000896458	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	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771903	SCV000904667	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 1424 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Marfan syndrome or other FBN1-related conditions (PMID: 9399842, 11748851, 14695540, 17657824, 17627385, 19293843, 23506379, 25812041). This variant has been found in an individual with isolated aortic aneurysms but the variant did not segregate with the phenotype in the family (PMID: 26621581). This variant has been reported in compound heterozygosity with p.Arg2680Cys in an individual affected with Marfan syndrome (PMID: 27582083), however, her affected son only carried the p.Arg2680Cys variant. This variant has been identified in 57/282832 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.
Mendelics	RCV000035194	SCV001139604	uncertain significance	Marfan syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001116398	SCV001274466	benign	Weill-Marchesani syndrome	2019-06-17	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001121321	SCV001279907	benign	Stiff skin syndrome	2019-06-17	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001121322	SCV001279908	benign	Geleophysic dysplasia	2019-06-17	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001121323	SCV001279909	benign	Acromicric dysplasia	2019-06-17	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001121324	SCV001279910	benign	Ectopia lentis 1, isolated, autosomal dominant	2019-06-17	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000035194	SCV001279911	uncertain significance	Marfan syndrome	2019-06-17	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000771903	SCV001279912	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-06-17	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.
Revvity Omics, Revvity	RCV000586163	SCV003833984	uncertain significance	not provided	2022-03-23	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000765222	SCV003919944	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	2022-01-25	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in at least 11 individuals with a clinical suspicion or diagnosis of Marfan syndrome, two of whom were reported as compound heterozygotes (Collod-Beroud 1998 PMID:9399842, Comeglio 2001 PMID:11748851, Biggin 2004 PMID:14695540, Comeglio 2007 PMID:17657824, Howarth 2007 PMID:17627385, Stheneur 2009 PMID:19293843, Turner 2009 PMID:19161152, Callier 2013 PMID:23506379, Arnaud 2017 PMID:27582083, Mattessi 2018 PMID:28655553). This variant is present in 0.2% (31/15280) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-48472617-G-C?dataset=gnomad_r3). Of note, the frequency of this variant is inconsistent with the expected incidence of this condition and several entries in ClinVar have noted this information in their classification (Variation ID:42355). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. A Likely Pathogenic variant at the same amino acid position (p.Pro1424Ser) has been previously reported (Arbustini 2005 PMID:16222657; Piqueras-Flores 2019 PMID:31053375). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
All of Us Research Program, National Institutes of Health	RCV000035194	SCV004814746	uncertain significance	Marfan syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 1424 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with Marfan syndrome or other FBN1-related conditions (PMID: 9399842, 11748851, 14695540, 17657824, 17627385, 19293843, 23506379, 25812041). This variant has been found in an individual with isolated aortic aneurysms but the variant did not segregate with the phenotype in the family (PMID: 26621581). This variant has been reported in compound heterozygosity with p.Arg2680Cys in an individual affected with Marfan syndrome (PMID: 27582083), however, her affected son only carried the p.Arg2680Cys variant. This variant has been identified in 57/282832 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.
CSER _CC_NCGL, University of Washington	RCV000035194	SCV000190205	uncertain significance	Marfan syndrome	2014-06-01	no assertion criteria provided	research
Center for Medical Genetics Ghent, University of Ghent	RCV000035194	SCV000787041	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755199	SCV000883028	uncertain significance	Congenital aneurysm of ascending aorta; Acute aortic dissection	2016-01-20	no assertion criteria provided	research