Submissions for variant NM_000138.5(FBN1):c.4130A>T (p.His1377Leu)

dbSNP: rs1238143005

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002023274	SCV002306938	uncertain significance	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1377 of the FBN1 protein (p.His1377Leu). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 1512931). This variant has not been reported in the literature in individuals affected with FBN1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database.
Fulgent Genetics, Fulgent Genetics	RCV002479784	SCV002777396	uncertain significance	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	2021-09-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003528350	SCV004357391	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-11-06	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 1377 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 not been identified 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	RCV004011145	SCV004827437	uncertain significance	Marfan syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 1377 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 not been identified 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.
PreventionGenetics, part of Exact Sciences	RCV004543683	SCV004790106	uncertain significance	FBN1-related disorder	2024-02-21	no assertion criteria provided	clinical testing	The FBN1 c.4130A>T variant is predicted to result in the amino acid substitution p.His1377Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as uncertain by multiple submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/1512931/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.