Submissions for variant NM_000138.5(FBN1):c.3422C>T (p.Pro1141Leu)

gnomAD frequency: 0.00054  dbSNP: rs2228241

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen FBN1 Variant Curation Expert Panel, ClinGen	RCV000266428	SCV003762207	benign	Marfan syndrome	2022-12-01	reviewed by expert panel	curation	NM_00138 c.3422C>T is a missense variant in FBN1 predicted to cause a substitution of a Proline by Leucine at amino acid 1141 (p.Pro1141Leu). This variant has been reported in the literature in at least 3 individuals in association with thoracic aortic aneurysm and dissection (TAAD), MASS syndrome, and features possibly consistent with Marfan syndrome (PMID: 10533071; PMID: 24740214; PMID: 26188975). This variant was also identified in an internal proband with isolated TAAD with a family history highly specific for Marfan syndrome, however it does not segregate with disease in an affected family member (BS4) and therefore PP4 cannot be used. This variant has been previously reported in ClinVar as benign, likely benign, and uncertain significance (Variation ID: 42334). This variant has been identified in 0.026% of individuals of European origin (BS1; https://gnomad.broadinstitute.org/ version 2.1.1). 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 two benign arguments PP2 cannot be used. 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: BS1, BS4
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035170	SCV000058812	benign	not specified	2019-01-02	criteria provided, single submitter	clinical testing	The p.Pro1141Leu variant in FBN1 is classified as benign because it has been ide ntified in 1.8% of Ashkenazi Jewish chromosomes by gnomAD. ACMG/AMP Criteria app lied: BA1.
GeneDx	RCV001703450	SCV000233788	likely benign	not provided	2020-12-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25812041, 26188975, 10533071, 24941995, 24740214, 27153395, 25203624)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228084	SCV000283622	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000251557	SCV000318115	benign	Familial thoracic aortic aneurysm and aortic dissection	2016-10-24	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.
Illumina Laboratory Services, Illumina	RCV000377620	SCV000392451	likely benign	Geleophysic dysplasia	2019-05-01	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000266428	SCV000392452	likely benign	Marfan syndrome	2019-05-01	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000251557	SCV000392454	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-05-01	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000279248	SCV000392455	likely benign	Stiff skin syndrome	2019-05-01	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000337118	SCV000392456	likely benign	Weill-Marchesani syndrome	2019-05-01	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000375425	SCV000392457	likely benign	Acromicric dysplasia	2019-05-01	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000292691	SCV000392458	likely benign	Ectopia lentis 1, isolated, autosomal dominant	2019-05-01	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000266428	SCV000781352	likely benign	Marfan syndrome	2016-11-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000251557	SCV000902137	benign	Familial thoracic aortic aneurysm and aortic dissection	2019-09-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000251557	SCV000903374	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-05-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001703450	SCV004129814	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	FBN1: BS1, BS2
Center for Medical Genetics Ghent, University of Ghent	RCV000266428	SCV000786963	uncertain significance	Marfan syndrome	2017-11-07	no assertion criteria provided	clinical testing
Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania	RCV001775003	SCV001573188	uncertain significance	Developmental cataract	2021-05-01	no assertion criteria provided	research