Submissions for variant NM_000138.5(FBN1):c.1289C>T (p.Pro430Leu)

gnomAD frequency: 0.00001  dbSNP: rs771134832

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472023	SCV000544820	likely benign	Marfan syndrome; Familial thoracic aortic aneurysm and aortic dissection	2024-01-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001189403	SCV000738810	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-06-16	criteria provided, single submitter	clinical testing	The p.P430L variant (also known as c.1289C>T), located in coding exon 10 of the FBN1 gene, results from a C to T substitution at nucleotide position 1289. The proline at codon 430 is replaced by leucine, an amino acid with similar properties, and is located in the proline-rich domain. This alteration was detected in a proband who also had a de novo FBN1 truncating alteration and presented with Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy. The p.P430L alteration was also detected in the proband's unaffected mother (Graul-Neumann LM et al. Am J Med Genet. 2010;152A(11):2749-55). Based on data from ExAC, the T allele has an overall frequency of less than 0.01% (2/105860). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6493 samples (12986 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659508	SCV000781330	uncertain significance	Connective tissue disorder	2016-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001189403	SCV001356688	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 430 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 Marfan syndrome, who also carried a pathogenic c.8155_8156delAA variant in the same gene, as well as in the unaffected mother (PMID: 20979188). This variant has been identified in 7/251276 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001810947	SCV002048137	uncertain significance	not provided	2020-10-20	criteria provided, single submitter	clinical testing	The FBN1 c.1289C>T; p.Pro430Leu variant (rs771134832), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 406265). This variant is found in the general population with an overall allele frequency of 0.003% (7/251,276 alleles) in the Genome Aggregation Database. The proline at codon 430 is weakly conserved, is not located in an EGF domain (InterPro), but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.279). Therefore, based on the available information, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV001810947	SCV002585497	likely benign	not provided	2022-08-01	criteria provided, single submitter	clinical testing	FBN1: PP2, BP4, BP5
GeneDx	RCV001810947	SCV004167940	uncertain significance	not provided	2023-11-02	criteria provided, single submitter	clinical testing	Reported in conjunction with a de novo FBN1 pathogenic frameshift variant in a patient diagnosed with Marfan syndrome and lipodystrophy with progeroid aspect (PMID: 20979188); however it is unclear if the p.(P430L) variant was in cis or trans with the second pathogenic FBN1 variant; In silico analysis supports that this missense variant does not alter protein structure/function; Does not affect a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); This variant is associated with the following publications: (PMID: 12938084, 20979188)
All of Us Research Program, National Institutes of Health	RCV004000729	SCV004823061	uncertain significance	Marfan syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 430 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 Marfan syndrome, who also carried a pathogenic c.8155_8156delAA variant in the same gene, as well as in the unaffected mother (PMID: 20979188). This variant has been identified in 7/251276 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.