Submissions for variant NM_000138.5(FBN1):c.2746G>A (p.Val916Met)

gnomAD frequency: 0.00007  dbSNP: rs373644734

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181468	SCV000233770	uncertain significance	not provided	2024-01-30	criteria provided, single submitter	clinical testing	Has been previously reported in one individual from a cohort of adolescent idiopathic scoliosis patients, and was also observed in 1/6,949 control alleles from a large population cohort (PMID: 24833718); however, no specific clinical or segregation details were provided; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24833718)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000631996	SCV000753099	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2025-01-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780231	SCV000917338	likely benign	not specified	2018-02-03	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.2746G>A (p.Val916Met) results in a conservative amino acid change located in the cb EGF-like #10 of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.000047 in 13/277068 control chromosomes, predominantly at a frequency of 0.00042 (10/24014 chrs) 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 3.73 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. The c.2746G>A has been reported in the literature in at least one individual with adolescent idiopathic scoliosis (Buchan_2014). These report(s) do 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV003528145	SCV004357429	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-09-07	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 916 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with adolescent idiopathic scoliosis (PMID: 24833718). This variant has been identified in 13/282608 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.
All of Us Research Program, National Institutes of Health	RCV003996678	SCV004814878	uncertain significance	Marfan syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 916 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with adolescent idiopathic scoliosis (PMID: 24833718). This variant has been identified in 13/282608 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.