Submissions for variant NM_000138.5(FBN1):c.2956G>A (p.Ala986Thr)

gnomAD frequency: 0.00107  dbSNP: rs112287730

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000029720	SCV004037325	benign	Marfan syndrome	2023-09-26	reviewed by expert panel	curation	NM_000138.5 c.2956G>A is a missense variant in FBN1 predicted to cause a substitution of an alanine by a threonine at amino acid 986 (p.Ala986Thr). This variant has been identified in numerous individuals with diagnoses or suspicion of Marfan syndrome in both the published literature and internal databases (PP4; PMIDs: 24793577, 26410935, 27582083, 28679693, 28387797; Bichat, Mayo, UZG, UZA); however, in at least 3 of these cases, another pathogenic variant in FBN1 was also present (BP2; Bichat). This variant has been previously reported in ClinVar as likely benign or benign by more than 20 laboratories (Variation ID: 36060). It is present in gnomAD v2.1.1 at a frequency of 0.19% (245/129170 alleles) in the European sub-population (BA1; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear about a predicted impact of this variant. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BA1, BP2, PP4. The pathogenic evidence code PP4 was not considered to be in conflict with this conclusion.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035156	SCV000058797	likely benign	not specified	2014-12-02	criteria provided, single submitter	clinical testing	p.Ala986Thr in exon 25 of FBN1: This variant is not expected to have clinical si gnificance because it has been identified in 0.198% (134/67678) of non-Finnish E uropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs112287730). This variant has been reported in 5 individua ls with clinical features of Marfan syndrom and/or connective tissue disorder, b ut was also identified in 2 unaffected relatives from two families (Rommel 2002, Frederic 2009, Aboni 2013, Lerner-Ellis 2014).
CSER _CC_NCGL, University of Washington	RCV000029720	SCV000212201	likely benign	Marfan syndrome	2015-03-11	criteria provided, single submitter	research
GeneDx	RCV001573319	SCV000233776	likely benign	not provided	2020-10-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16220557, 24793577, 12402346, 19370756, 27582083, 26410935, 28387797, 23608731, 28679693)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000029720	SCV000257633	benign	Marfan syndrome	2015-07-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232842	SCV000283615	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000143891	SCV000317391	benign	Familial thoracic aortic aneurysm and aortic dissection	2015-02-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Eurofins Ntd Llc (ga)	RCV000035156	SCV000344374	likely benign	not specified	2016-08-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000362429	SCV000392508	benign	Geleophysic dysplasia	2018-01-12	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	RCV000143891	SCV000392509	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-01-12	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	RCV000309065	SCV000392510	benign	Ectopia lentis 1, isolated, autosomal dominant	2018-01-12	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	RCV000366054	SCV000392511	benign	Acromicric dysplasia	2018-01-12	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	RCV000322108	SCV000392513	benign	Weill-Marchesani syndrome	2018-01-12	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	RCV000029720	SCV000392514	benign	Marfan syndrome	2018-01-12	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	RCV000268151	SCV000392515	benign	Stiff skin syndrome	2018-01-12	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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659523	SCV000781349	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000143891	SCV000902995	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-03-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000029720	SCV001139616	likely benign	Marfan syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000143891	SCV001333957	benign	Familial thoracic aortic aneurysm and aortic dissection	2017-11-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001573319	SCV002497785	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	FBN1: BS1
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000659523	SCV002566520	likely benign	Connective tissue disorder	2021-12-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003227609	SCV003924108	likely benign	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	2021-03-30	criteria provided, single submitter	clinical testing	FBN1 NM_000138.4 exon 25 p.Ala986Thr (c.2956G>A): This variant has been reported in the literature in at least 4 individuals with features of connective tissues disorders (Lerner-Ellis 2014 PMID:24793577, Arnaud 2017 PMID:27582083, Cousin 2017 PMID:28679693, Girdauskas 2017 PMID:28387797). However, this variant is also present in 0.1% (20/10474) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-48489977-C-T?dataset=gnomad_r3) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:36060). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029720	SCV000052373	benign	Marfan syndrome	2012-03-13	no assertion criteria provided	clinical testing
Blueprint Genetics	RCV000143891	SCV000188760	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2013-12-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528137	SCV000302546	likely benign	FBN1-related disorder	2020-05-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Center for Medical Genetics Ghent, University of Ghent	RCV000029720	SCV000786906	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573319	SCV001799013	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000035156	SCV001807853	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001573319	SCV001928720	likely benign	not provided		no assertion criteria provided	clinical testing