Submissions for variant NM_001105206.3(LAMA4):c.4792G>T (p.Ala1598Ser)

gnomAD frequency: 0.00015  dbSNP: rs202176359

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222537	SCV000271897	uncertain significance	not specified	2015-09-09	criteria provided, single submitter	clinical testing	The p.Ala1591Ser variant in LAMA4 has been identified by our laboratory in 1 chi ld with LVNC who carried another variant more likely responsible for disease. Th e p.Ala1591Ser variant has been identified in 18/66692 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2 02176359). Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein. In summary, the clini cal significance of the p.Ala1591Ser variant is uncertain.
Invitae	RCV000537963	SCV000654019	uncertain significance	Dilated cardiomyopathy 1JJ	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1591 of the LAMA4 protein (p.Ala1591Ser). This variant is present in population databases (rs202176359, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 30847666). This variant is also known as c.4792G>T (p.Ala1598Ser). ClinVar contains an entry for this variant (Variation ID: 228783). 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 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.
GeneDx	RCV001589129	SCV001817067	uncertain significance	not provided	2020-06-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 228783; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30847666)
Ambry Genetics	RCV002327088	SCV002633735	uncertain significance	Cardiovascular phenotype	2022-03-28	criteria provided, single submitter	clinical testing	The p.A1591S variant (also known as c.4771G>T), located in coding exon 33 of the LAMA4 gene, results from a G to T substitution at nucleotide position 4771. The alanine at codon 1591 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. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000537963	SCV002767841	uncertain significance	Dilated cardiomyopathy 1JJ	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3C-VUS. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established although current evidence in the literature suggests loss of function as a mechanism of disease (PMIDs: 16204254, 17646580). (I) 0107 - This gene is associated with autosomal dominant disease, however a recent review has classified the inheritance pattern associated with LAMA4 as unknown (PMID: 23274168). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (57 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.Ala1598Gly: 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Laminin G domain (NCBI conserved domain). (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 previously been classified as a variant of uncertain significance (ClinVar, PMID: 30847666). (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
Fulgent Genetics, Fulgent Genetics	RCV000537963	SCV002778396	uncertain significance	Dilated cardiomyopathy 1JJ	2021-08-09	criteria provided, single submitter	clinical testing