Submissions for variant NM_000138.5(FBN1):c.3454G>A (p.Ala1152Thr)

gnomAD frequency: 0.00016  dbSNP: rs140890215

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000243495	SCV000302551	likely benign	not specified		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044344	SCV001208135	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001184767	SCV001350828	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1152 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 an individual affected with thoracic aortic aneurysm and dissection with penetrating atherosclerotic ulcers (PMID: 29543232). This variant has been identified in 14/282878 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.
GeneDx	RCV001658158	SCV001874745	uncertain significance	not provided	2021-07-20	criteria provided, single submitter	clinical testing	Has been reported as a variant of uncertain significance in an individual with TAAD (Weerakkody et al., 2018); 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); Reported in ClinVar (ClinVar Variant ID# 255292; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 26582918, 29543232)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000243495	SCV002041896	likely benign	not specified	2024-08-12	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.3454G>A (p.Ala1152Thr) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of 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 1614192 control chromosomes, predominantly at a frequency of 0.00023 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011). c.3454G>A has been reported in the literature as a VUS in a setting of multigene panel testing in an individual from a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta (Weerakkody_2018). This report does not provide unequivocal conclusions about association of the variant with Marfan Syndrome or other FBN1-related disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29543232). ClinVar contains an entry for this variant (Variation ID: 255292). Based on the evidence outlined above, the variant was classified as likely benign.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224240	SCV003919952	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	2022-12-29	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in one individual with TAAD (Weerakkody 2018 PMID: 29543232). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.04% [6/15284], and in 1 homozygote; https://gnomad.broadinstitute.org/variant/15-48487321-C-T?dataset=gnomad_r3). It is also present in ClinVar, with classifications ranging from uncertain significance to likely benign (Variation ID: 255292). Evolutionary conservation and computational prediction tools are unclear for this variant. 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.
All of Us Research Program, National Institutes of Health	RCV003998948	SCV004814804	uncertain significance	Marfan syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1152 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 an individual affected with thoracic aortic aneurysm and dissection with penetrating atherosclerotic ulcers (PMID: 29543232). This variant has been identified in 14/282878 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	RCV001184767	SCV005032584	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-10-06	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.