Submissions for variant NM_000428.3(LTBP2):c.220G>C (p.Glu74Gln)

gnomAD frequency: 0.00013  dbSNP: rs79886273

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000576473	SCV000678224	uncertain significance	Weill-Marchesani syndrome 3	2017-08-01	criteria provided, single submitter	clinical testing	LTBP2 NM_000428.2 exon1 p.Glu74Gln (c.220G>C): This variant has not been reported in the literature but is present in 50/111256 European chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs79886273). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Laboratory Services, Illumina	RCV001121381	SCV001279987	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.
Illumina Laboratory Services, Illumina	RCV001121382	SCV001279988	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.
Invitae	RCV001853826	SCV002301879	uncertain significance	not provided	2022-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 74 of the LTBP2 protein (p.Glu74Gln). This variant is present in population databases (rs79886273, 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: 487467). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	RCV002529029	SCV003676141	uncertain significance	Inborn genetic diseases	2022-05-04	criteria provided, single submitter	clinical testing	The c.220G>C (p.E74Q) alteration is located in exon 1 (coding exon 1) of the LTBP2 gene. This alteration results from a G to C substitution at nucleotide position 220, causing the glutamic acid (E) at amino acid position 74 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224339	SCV003920165	uncertain significance	Glaucoma 3, primary congenital, D; Weill-Marchesani syndrome 3; Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma	2021-03-30	criteria provided, single submitter	clinical testing	LTBP2 NM_000428.2 exon1 p.Glu74Gln (c.220G>C): This variant has not been reported in the literature but is present in 50/111256 European chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs79886273). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.