Submissions for variant NM_000428.3(LTBP2):c.1301C>T (p.Pro434Leu)

gnomAD frequency: 0.00009  dbSNP: rs371940681

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000305545	SCV000388673	uncertain significance	Glaucoma 3, primary congenital, D	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000341687	SCV000388674	uncertain significance	Weill-Marchesani syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics, Fulgent Genetics	RCV002504081	SCV002800742	uncertain significance	Glaucoma 3, primary infantile, B; Glaucoma 3, primary congenital, D; Weill-Marchesani syndrome 3; Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma	2021-10-12	criteria provided, single submitter	clinical testing
Invitae	RCV002520920	SCV003515742	uncertain significance	not provided	2022-08-10	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 434 of the LTBP2 protein (p.Pro434Leu). This variant is present in population databases (rs371940681, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with LTBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 314311). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV003165847	SCV003878234	likely benign	Inborn genetic diseases	2023-01-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003338571	SCV004048219	uncertain significance	Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma		criteria provided, single submitter	clinical testing	The missense variant p.P434L in LTBP2 (NM_000428.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. There is a moderate physicochemical difference between proline and leucine. The p.P434L missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The nucleotide c.1301 in LTBP2 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.