Submissions for variant NM_001105206.3(LAMA4):c.1673C>T (p.Ala558Val)

gnomAD frequency: 0.00013  dbSNP: rs137893207

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724410	SCV000226090	uncertain significance	not provided	2015-01-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000724410	SCV000250554	uncertain significance	not provided	2019-10-29	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 by several other clinical laboratories (ClinVar Variant ID#194372; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000197506	SCV000271893	uncertain significance	not specified	2015-11-12	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ala551Val var iant in LAMA4 has not been previously reported in individuals with cardiomyopath y, but has been identified in 6/62116 European chromosomes by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs137893207). Alanin e (Ala) at position 551 is not conserved in evolutionarily distant species with 7 reptiles and birds having a valine (Val) at that position, raising the possibi lity that this change may be tolerated. Other computational prediction tools sug gest that the p.Ala551Val variant may not impact the protein, though this inform ation is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Ala551Val variant is uncertain, these data sugges t that it is more likely to be benign.
Invitae	RCV000535614	SCV000654002	uncertain significance	Dilated cardiomyopathy 1JJ	2023-08-01	criteria provided, single submitter	clinical testing	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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 194372). This variant has not been reported in the literature in individuals affected with LAMA4-related conditions. This variant is present in population databases (rs137893207, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 551 of the LAMA4 protein (p.Ala551Val).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000724410	SCV000885646	uncertain significance	not provided	2017-07-07	criteria provided, single submitter	clinical testing	The p.Ala551Val variant (rs137893207) has not been reported in the medical literature; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 194372). It is listed in the Genome Aggregation Database (gnomAD) browser with an overall frequency of 0.029% (identified in 7 out of 23,984 chromosomes). The alanine at codon 551 is weakly conserved considering 12 species (Alamut software v2.9), and computational analyses suggest this variant does not have a significant effect on LAMA4 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Ala551Val variant cannot be determined with certainty.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770218	SCV000901648	uncertain significance	Cardiomyopathy	2016-11-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399630	SCV002704681	uncertain significance	Cardiovascular phenotype	2023-06-14	criteria provided, single submitter	clinical testing	The p.A551V variant (also known as c.1652C>T), located in coding exon 13 of the LAMA4 gene, results from a C to T substitution at nucleotide position 1652. The alanine at codon 551 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available 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.
Fulgent Genetics, Fulgent Genetics	RCV000535614	SCV002784276	uncertain significance	Dilated cardiomyopathy 1JJ	2021-08-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000724410	SCV003917091	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	LAMA4: BP4, BS2
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000197506	SCV000280171	uncertain significance	not specified	2014-04-15	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LAMA4 p.Ala551Val Given the weak gene-phenotype evidence, the lack of case data and presence in unselected individuals (albeit rare), we consider this variant a variant of uncertain significance. 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 is novel. The variant was reported online in 8 of 57,245 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of July 22nd, 2015). Specifically, the variant was observed in 6 of 31,058 European individuals, 1 of 5057 African individuals, and 1 of 5477 Latino individuals. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012).