Submissions for variant NM_001105206.3(LAMA4):c.2417G>A (p.Arg806Gln)

dbSNP: rs1554334150

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000621174	SCV000736601	uncertain significance	Cardiovascular phenotype	2023-02-12	criteria provided, single submitter	clinical testing	The p.R799Q variant (also known as c.2396G>A), located in coding exon 18 of the LAMA4 gene, results from a G to A substitution at nucleotide position 2396. The arginine at codon 799 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and glutamine is the reference amino acid in other 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.
GeneDx	RCV000786337	SCV002575332	uncertain significance	not provided	2022-09-22	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function
Fulgent Genetics, Fulgent Genetics	RCV002506497	SCV002816387	uncertain significance	Dilated cardiomyopathy 1JJ	2021-10-11	criteria provided, single submitter	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786337	SCV000925113	uncertain significance	not provided	2017-06-20	no assertion criteria provided	provider interpretation	Given the weak gene-disease relationship and lack of case data, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The LAMA4 gene has only limited evidence to associate it with cardiomyopathy. LAMA4 variants have been reported in association with DCM, however only minimal evidence is available. Knoll et al (2007) identified LAMA4 as a candidate gene after a zebrafish screen then sequenced in patients with severe DCM and found a missense variant and a nonsense variant. We have not evaluated the strength of this evidence. This variant has not been seen in any cases of cardiomyopathy. I could find no published reports of the variant, nor did it have an entry in ClinVar. In silico analyses do not agree on the potential impact of this missense change on protein function. The variant is reported in 4 of 122,963 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, the variant was reported in 1 of 2740 individuals (MAF 0.01%) in the "Other" ancestry, 2 of 16,788 (MAF 0.0059%) individuals of Latino ancestry, and 1 of 15,391 individuals (MAF 0.0032%) of South Asian ancestry.