Submissions for variant NM_001105206.3(LAMA4):c.167C>T (p.Ala56Val)

gnomAD frequency: 0.00006  dbSNP: rs372763422

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000651435	SCV000773286	uncertain significance	Dilated cardiomyopathy 1JJ	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 56 of the LAMA4 protein (p.Ala56Val). This variant is present in population databases (rs372763422, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LAMA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 541220). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV001577946	SCV001805445	uncertain significance	not provided	2021-08-06	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge Observed in 0.011% (26/229,608) alleles in large population cohorts (Lek et al., 2016) In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Ambry Genetics	RCV002397305	SCV002714487	uncertain significance	Cardiovascular phenotype	2022-05-04	criteria provided, single submitter	clinical testing	The p.A56V variant (also known as c.167C>T), located in coding exon 1 of the LAMA4 gene, results from a C to T substitution at nucleotide position 167. The alanine at codon 56 is replaced by valine, an amino acid with similar properties. This amino acid position is not 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.
Fulgent Genetics, Fulgent Genetics	RCV000651435	SCV002816863	uncertain significance	Dilated cardiomyopathy 1JJ	2021-10-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150325	SCV003838075	likely benign	Cardiomyopathy	2021-06-09	criteria provided, single submitter	clinical testing