Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003117616 | SCV003787182 | uncertain significance | not provided | 2023-09-23 | 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 2948 of the LAMA5 protein (p.Gly2948Ser). This variant is present in population databases (rs529211517, gnomAD 0.2%). This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 29534211). ClinVar contains an entry for this variant (Variation ID: 684687). 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 expected to disrupt LAMA5 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. |
| Prevention |
RCV003413669 | SCV004118309 | uncertain significance | LAMA5-related disorder | 2022-12-21 | criteria provided, single submitter | clinical testing | The LAMA5 c.8842G>A variant is predicted to result in the amino acid substitution p.Gly2948Ser. This variant was reported in the homozygous state in an individual with nephrotic syndrome (Braun et al 2019. PubMed ID: 29534211). This variant is reported in 0.25% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-60888257-C-T), which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Victorian Clinical Genetics Services, |
RCV002286424 | SCV005398267 | uncertain significance | Nephrotic syndrome, IIa 26 | 2024-10-10 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nephrotic syndrome, type 26 (MIM#620049) and focal segmental glomerular sclerosis (FSGS; PMID: 24130771). The mechanism of disease associated with complex multisystem syndrome due to ECM dysfunction is currently unclear. (I) 0106 - This gene is associated with autosomal recessive disease. There are limited reports on autosomal dominant FSGS and complex multisystem syndrome due to ECM dysfunction (PMID: 24130771, 28735299). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (87 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0600 - Variant is located in the annotated laminin G-like 2 domain (UniProt, PMID: 35419533). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported twice as a VUS in ClinVar, and has been observed in a homozygous individual with nephrotic syndrome (PMID: 29534211). (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 |
| Ambry Genetics | RCV004986651 | SCV005613348 | uncertain significance | Inborn genetic diseases | 2024-10-28 | criteria provided, single submitter | clinical testing | The c.8842G>A (p.G2948S) alteration is located in exon 65 (coding exon 65) of the LAMA5 gene. This alteration results from a G to A substitution at nucleotide position 8842, causing the glycine (G) at amino acid position 2948 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Yale Center for Mendelian Genomics, |
RCV000845203 | SCV000987139 | uncertain significance | Nephrotic syndrome | 2018-03-09 | no assertion criteria provided | literature only | |
| OMIM | RCV002286424 | SCV002576380 | pathogenic | Nephrotic syndrome, IIa 26 | 2022-10-13 | no assertion criteria provided | literature only |