Submissions for variant NM_001105206.3(LAMA4):c.1437_1442dup (p.Asp480_Tyr481dup)

dbSNP: rs782294432

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497769	SCV000590259	uncertain significance	not provided	2017-06-06	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the LAMA4 gene. The c.1416_1421dupTGACTA variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 8/8624 (0.1%) alleles from individuals of East Asian ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). The c.1416_1421dupTGACTA variant results in a duplication of two amino acids. However, as this is an in-frame duplication, it is not expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae	RCV000793602	SCV000932964	uncertain significance	Dilated cardiomyopathy 1JJ	2022-07-19	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with LAMA4-related conditions. This variant is present in population databases (rs782294432, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant, c.1416_1421dup, results in the insertion of 2 amino acid(s) of the LAMA4 protein (p.Asp473_Tyr474dup), but otherwise preserves the integrity of the reading frame. ClinVar contains an entry for this variant (Variation ID: 432525). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown.
Ambry Genetics	RCV002395204	SCV002699712	uncertain significance	Cardiovascular phenotype	2022-04-04	criteria provided, single submitter	clinical testing	The c.1416_1421dupTGACTA variant (also known as p.D473_Y474dup), located in coding exon 11 of the LAMA4 gene, results from an in-frame duplication of TGACTA at nucleotide positions 1416 to 1421. This results in the duplication of 2 extra residues (DY) between codons 473 and 474. This amino acid region is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.