Submissions for variant NM_000138.5(FBN1):c.76G>C (p.Asp26His)

gnomAD frequency: 0.00018  dbSNP: rs146267697

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001183094	SCV001348749	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine at codon 26 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 not been reported in individuals affected with FBN1-related disorders in the literature. This variant has been identified in 13/282850 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001315149	SCV001505707	benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-11-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004008350	SCV004823160	uncertain significance	Marfan syndrome	2024-05-24	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the propeptide sequence of the FBN1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 13/277192 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782664	SCV005395187	likely benign	not specified	2024-09-23	criteria provided, single submitter	clinical testing	Variant summary: FBN1 c.76G>C (p.Asp26His) results in a non-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 2.3e-05 in 1614082 control chromosomes, predominantly at a frequency of 0.00048 within the African or African-American subpopulation in the gnomAD database (v4). The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011). To our knowledge, no occurrence of c.76G>C in individuals affected with Marfan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 922799). Based on the evidence outlined above, the variant was classified as likely benign.