Submissions for variant NM_000138.5(FBN1):c.3514G>A (p.Val1172Met)

gnomAD frequency: 0.00017  dbSNP: rs200125037

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035175	SCV000058817	uncertain significance	not specified	2008-06-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000587741	SCV000233993	uncertain significance	not provided	2023-06-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter 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); Identified in a patient with features of Marfan syndrome in published literature (Lerner-Ellis et al., 2014); however, this individual also harbored a second pathogenic variant in the FBN1 gene but phase was not specified; This variant is associated with the following publications: (PMID: 12938084, 24793577)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035175	SCV000695518	uncertain significance	not specified	2023-07-31	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.3514G>A (p.Val1172Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251448 control chromosomes, predominantly at a frequency of 0.00086 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7.64 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 a benign polymorphism found primarily in populations of African or African-American origin. c.3514G>A has been reported in the literature in individuals affected with Marfan Syndrome, without strong evidence for causality (eg. Lerner-Ellis_2014). This report does not provide unequivocal conclusions about association of the variant with Marfan Syndrome. 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: 24793577, 33448881). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: three submitters classified the variant as VUS while three classified the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631923	SCV000753026	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2023-06-23	criteria provided, single submitter	clinical testing
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659527	SCV000781354	likely benign	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170779	SCV001333385	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2018-07-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587741	SCV001473495	uncertain significance	not provided	2019-09-19	criteria provided, single submitter	clinical testing	The FBN1 c.3514G>A; p.Val1172Met variant (rs200125037) is reported in the literature in an individual affected with a suspected aortopathy (Lerner-Ellis 2014). However, the affected individual with this variant was also reported to carry a different pathogenic FBN1 variant (Lerner-Ellis 2014). The p.Val1172Met variant is found in the African population with an overall allele frequency of 0.06% (16/24964 alleles) in the Genome Aggregation Database. The valine at codon 1172 is weakly conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, due to limited information, the clinical significance of the p.Val1172Met variant is uncertain at this time. References: Lerner-Ellis JP et al. The spectrum of FBN1, TGFßR1, TGFßR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD). Mol Genet Metab. 2014 Jun;112(2):171-6.
Color Diagnostics, LLC DBA Color Health	RCV001170779	SCV002052634	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-04-21	criteria provided, single submitter	clinical testing