Submissions for variant NM_006329.4(FBLN5):c.1051C>T (p.Arg351Trp)

gnomAD frequency: 0.00010  dbSNP: rs28939073

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000005815	SCV001139500	uncertain significance	Macular degeneration, age-related, 3	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000005815	SCV001278231	uncertain significance	Macular degeneration, age-related, 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001119789	SCV001278232	uncertain significance	Cutis laxa	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001577844	SCV001805315	uncertain significance	not provided	2021-08-18	criteria provided, single submitter	clinical testing	Identified in a patient with age-related macular degeneration in the published literature (Stone et al., 2004) Functional data suggests that R351W indicates increased self-association of the dimers (Jones et al., 2010), though additional studies are need to elucidate the pathogenicity of R351W In silico analysis supports that this missense variant has a deleterious effect on protein structure/function Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 5481; Landrum et al., 2016) This variant is associated with the following publications: (PMID: 20007835, 15269314, 21576112)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001577844	SCV002251354	uncertain significance	not provided	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 351 of the FBLN5 protein (p.Arg351Trp). This variant is present in population databases (rs28939073, gnomAD 0.03%). This missense change has been observed in individual(s) with age-related macular degeneration (PMID: 15269314). ClinVar contains an entry for this variant (Variation ID: 5481). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBLN5 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect FBLN5 function (PMID: 16652333). 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251883	SCV002523474	uncertain significance	See cases	2019-04-22	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, PP3
Fulgent Genetics, Fulgent Genetics	RCV002490323	SCV002792778	uncertain significance	Macular degeneration, age-related, 3; Cutis laxa, autosomal recessive, type 1A; Cutis laxa, autosomal dominant 2; Charcot-Marie-Tooth disease, demyelinating, IIA 1H	2021-10-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700191	SCV005202531	uncertain significance	not specified	2024-07-12	criteria provided, single submitter	clinical testing	Variant summary: FBLN5 c.1051C>T (p.Arg351Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251396 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FBLN5 causing FBLN5-Related Disorders, allowing no conclusion about variant significance. c.1051C>T has been reported in the literature in individuals affected with FBLN5-Related Disorders (Stone_2004, Wasowska_2023). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Jones_2010, Lotery_2007). The following publications have been ascertained in the context of this evaluation (PMID: 20007835, 16652333, 15269314, 37761846). ClinVar contains an entry for this variant (Variation ID: 5481). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
OMIM	RCV000005815	SCV000025997	pathogenic	Macular degeneration, age-related, 3	2004-07-22	no assertion criteria provided	literature only
Inherited Neuropathy Consortium Ii, University Of Miami	RCV003447073	SCV004174405	uncertain significance	Age-related macular degeneration	2016-01-06	no assertion criteria provided	literature only