Submissions for variant NM_003476.5(CSRP3):c.265G>A (p.Gly89Ser)

dbSNP: rs367827746

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150368	SCV000197494	uncertain significance	not specified	2013-08-23	criteria provided, single submitter	clinical testing	The Gly89Ser variant in CSRP3 has not been reported in individuals with cardiomy opathy, but has been identified in 1/4398 African American chromosomes by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein . Additional information is needed to fully assess the clinical significance of the Gly89Ser variant.
Illumina Laboratory Services, Illumina	RCV001107933	SCV001265121	uncertain significance	Hypertrophic cardiomyopathy 12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001346369	SCV001540565	uncertain significance	Hypertrophic cardiomyopathy 12; Dilated cardiomyopathy 1M	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 89 of the CSRP3 protein (p.Gly89Ser). This variant is present in population databases (rs367827746, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CSRP3-related conditions. ClinVar contains an entry for this variant (Variation ID: 163012). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	RCV002453481	SCV002739898	uncertain significance	Cardiovascular phenotype	2022-03-14	criteria provided, single submitter	clinical testing	The p.G89S variant (also known as c.265G>A), located in coding exon 2 of the CSRP3 gene, results from a G to A substitution at nucleotide position 265. The glycine at codon 89 is replaced by serine, an amino acid with similar properties. This amino acid position is well 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001107933	SCV005086629	uncertain significance	Hypertrophic cardiomyopathy 12	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (9 heterozygotes, 0 homozygotes). (I) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (5 heterozygotes, 0 homozygotes). (I) 0310 - Variant is present in gnomAD (v2) >=0.001 and <0.01 for a dominant condition (9 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 – Another missense variant, comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Gly89Cys) has previously been classified a VUS, however no clinical information was provided (ClinVar, LOVD) (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has previously been classified as a VUS with no further clinical information provided (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign