Submissions for variant NM_000138.5(FBN1):c.7846A>G (p.Ile2616Val)

gnomAD frequency: 0.00009  dbSNP: rs143677764

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552622	SCV000627999	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2025-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000593778	SCV000701928	uncertain significance	not provided	2017-10-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001118561	SCV001276852	benign	Weill-Marchesani syndrome	2019-08-14	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	RCV001118562	SCV001276853	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-08-14	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	RCV001118563	SCV001276854	benign	Geleophysic dysplasia	2019-08-14	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	RCV001118564	SCV001276855	benign	Ectopia lentis 1, isolated, autosomal dominant	2019-08-14	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	RCV000148491	SCV001276856	likely benign	Marfan syndrome	2019-08-14	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001118565	SCV001276857	benign	Stiff skin syndrome	2019-08-14	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	RCV001118566	SCV001276858	benign	Acromicric dysplasia	2019-08-14	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.
Color Diagnostics, LLC DBA Color Health	RCV001118562	SCV001358496	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-11-18	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 2616 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with Marfan syndrome (PMID: 17627385). This variant has been identified in 15/282590 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	RCV001118562	SCV004085946	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-09-05	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700472	SCV005204653	likely benign	not specified	2024-06-19	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.7846A>G (p.Ile2616Val) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 1461846 control chromosomes, predominantly at a frequency of 0.00041 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.64 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011). c.7846A>G has been reported in the literature in at least one individual affected with Marfan Syndrome (Howarth_2007). 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: 24055113, 28659821, 17627385). ClinVar contains an entry for this variant (Variation ID: 161237). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000593778	SCV005436635	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	FBN1: BP4
CSER _CC_NCGL, University of Washington	RCV000148491	SCV000190197	uncertain significance	Marfan syndrome	2014-06-01	no assertion criteria provided	research