Submissions for variant NM_000138.5(FBN1):c.6700G>A (p.Val2234Met)

gnomAD frequency: 0.00078  dbSNP: rs112084407

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035252	SCV000058898	uncertain significance	not specified	2011-07-01	criteria provided, single submitter	clinical testing	The 6700G>A (Val2234Met) variant has been reported in the literature in one indi vidual meeting the Ghent clinical criteria for Marfan syndrome (Tjeldhorn 2006, Rand-Hendriksen 2007). However, this individual also carried a second FBN1 varia nt (Asp1113Gly) that was found in four affected family members and who were all negative for the Val2234Met variant (Rand-Hendriksen 2007). This variant has bee n identified by our laboratory in one family; two family members that are report edly minimally affected with some clinical features of Marfan syndrome carry thi s variant. Valine (Val) at amino acid position 2234 is not completely conserved in other mammals or distantly related species (cow, dog, elephant, chicken and f rog carry an alanine; opossum carries an isoleucine; fish carries a threonine). Furthermore, this variant has been reported in dbSNP (rs112084407) with a minor allele frequency of 0.002. Collectively, these data reduce the likelihood that t his change is pathogenic. However, in the absence of additional data, we cannot conclusively determine the clinical significance of this variant at this time, t hough we lean towards a likely benign role.
GeneDx	RCV000726908	SCV000233880	likely benign	not provided	2021-05-27	criteria provided, single submitter	clinical testing	Reported in ClinVar (ClinVar Variant ID#36104; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 24941995, 17657824, 17663468, 21883168, 25812041, 24055113, 17253931, 32679894)
Ambry Genetics	RCV000769627	SCV000317882	benign	Familial thoracic aortic aneurysm and aortic dissection	2014-10-29	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	RCV000273547	SCV000392196	likely benign	Geleophysic dysplasia	2018-05-01	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	RCV000310000	SCV000392197	likely benign	Acromicric dysplasia	2018-05-01	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	RCV000029766	SCV000392198	likely benign	Marfan syndrome	2018-05-01	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). 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	RCV000270709	SCV000392199	likely benign	Ectopia lentis 1, isolated, autosomal dominant	2018-05-01	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081774	SCV000557055	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000726908	SCV000704103	uncertain significance	not provided	2017-01-11	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659568	SCV000781402	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000029766	SCV000807914	likely benign	Marfan syndrome	2018-06-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769627	SCV000901025	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-03-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769627	SCV000903361	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-04-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000029766	SCV001139590	benign	Marfan syndrome	2023-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726908	SCV001149448	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	FBN1: BS1
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000726908	SCV001157313	benign	not provided	2023-10-13	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000035252	SCV001422582	benign	not specified	2020-01-22	criteria provided, single submitter	curation	The p.Val2234Met variant in FBN1 has been reported in at least 1 Norwegian and 1 other individual with Marfan Syndrome (PMID: 17663468, 17253931; Lazalde et al. 2017), but has been identified in 0.1281% (165/128814) of European (non-Finnish) chromosomes, 0.09601% (34/35414) of Latino chromosomes, and 0.01602% (4/24966) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs112084407). This variant has also been reported benign, likely benign, and a VUS in ClinVar (Variation ID: 36104). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Val2234Met variant did not segregate with Marfan Syndrome in 4 affected relatives of an individual with the variant, suggesting that this variant is not pathogenic for Marfan Syndrome (PMID: 17663468). Marfan Syndrome has been reported to have high clinical penetrance (PMID: 20301510) and the p.Val2234Met variant has been reported in the literature in at least 4 individuals without Marfan Syndrome, increasing the chance that this variant is benign (PMID: 25812041, 25637381; Variation ID: 36104). Two affected individuals with this variant have an alternative molecular basis for Marfan Syndrome, suggesting that this variant may not be pathogenic (PMID: 17663468; Lazalde et al. 2017). The number of missense variants reported in FBN1 in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, this variant meets criteria to be classified as benign for Marfan Syndrome in an autosomal dominant manner based on its frequency in the general population and multiple occurrences in individuals without Marfan Syndrome. ACMG/AMP Criteria applied: BS2, BS4, BS1, BP5 (Richards 2015).
Molecular Genetics, Royal Melbourne Hospital	RCV000029766	SCV004812650	likely benign	Marfan syndrome	2023-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029766	SCV000052419	benign	Marfan syndrome	2015-06-12	no assertion criteria provided	clinical testing
CSER _CC_NCGL, University of Washington	RCV000029766	SCV000190200	likely benign	Marfan syndrome	2016-08-15	no assertion criteria provided	research	Originally interpreted based on literature review PMID: 25637381. Found in patient having exome sequencing for an unrelated indication. No known history of Marfan syndrome.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000035252	SCV001808277	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000726908	SCV001976252	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532415	SCV004719718	likely benign	FBN1-related disorder	2022-02-10	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).