Submissions for variant NM_001105206.3(LAMA4):c.3506C>T (p.Pro1169Leu)

gnomAD frequency: 0.00002  dbSNP: rs730880123

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001370376	SCV001566853	uncertain significance	Dilated cardiomyopathy 1JJ	2021-01-06	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with LAMA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 180393). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is present in population databases (rs730880123, ExAC 0.003%). This sequence change replaces proline with leucine at codon 1162 of the LAMA4 protein (p.Pro1162Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001370376	SCV002048037	uncertain significance	Dilated cardiomyopathy 1JJ	2020-10-04	criteria provided, single submitter	clinical testing	The LAMA4 p.Pro1162Leu variant (rs730880123), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 180393). This variant is found in the general population with an overall allele frequency of 0.001% (3/250,834 alleles) in the Genome Aggregation Database. The proline at codon 1162 is highly conserved (Alamut v.2.11) and computational analyses (SIFT, PolyPhen-2) predict conflicting effects of this variant on protein structure/function. Based on the available information, the clinical significance of this variant is uncertain.
Ambry Genetics	RCV002453530	SCV002613321	uncertain significance	Cardiovascular phenotype	2022-03-14	criteria provided, single submitter	clinical testing	The p.P1162L variant (also known as c.3485C>T), located in coding exon 25 of the LAMA4 gene, results from a C to T substitution at nucleotide position 3485. The proline at codon 1162 is replaced by leucine, an amino acid with similar properties. This variant was detected in a dilated cardiomyopathy cohort and a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309).This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Blueprint Genetics	RCV000157280	SCV000207011	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2014-08-04	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001698980	SCV001917566	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001698980	SCV001960025	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001698980	SCV001967343	uncertain significance	not provided		no assertion criteria provided	clinical testing