Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000037334 | SCV000060991 | uncertain significance | not specified | 2013-01-13 | criteria provided, single submitter | clinical testing | Variant classified as Uncertain Significance - Favor Benign. The His457Asp varia nt in LAMA4 has not been reported in the literature, but has been identified by our laboratory in 1 individual with HCM, who also carried another variant likely to be disease-causing (LMM unpublished data). This variant is listed in dbSNP w ithout frequency information (dbSNP rs151119304) and has not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS), though it may be co mmon in other populations. Histidine (His) at position 457 is not well conserved in evolution, including in mammals, which suggests that a change at this positi on may be tolerated. Other computational analyses (biochemical amino acid proper ties, AlignGVGD, PolyPhen2, and SIFT) also suggest that the variant may not impa ct the protein, though this information is not predictive enough to rule out pat hogenicity. In summary, the available data suggests that this variant is more li kely benign, but additional studies are needed to fully assess the clinical sign ificance of the His457Asp variant. |
Invitae | RCV000651446 | SCV000773297 | uncertain significance | Dilated cardiomyopathy 1JJ | 2023-04-06 | 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: 44346). This variant has not been reported in the literature in individuals affected with LAMA4-related conditions. This variant is present in population databases (rs151119304, gnomAD 0.01%). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 457 of the LAMA4 protein (p.His457Asp). |
CHEO Genetics Diagnostic Laboratory, |
RCV001170697 | SCV001333291 | uncertain significance | Cardiomyopathy | 2018-09-11 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000651446 | SCV002785240 | uncertain significance | Dilated cardiomyopathy 1JJ | 2021-08-12 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV003298066 | SCV003988566 | uncertain significance | Cardiovascular phenotype | 2023-04-09 | criteria provided, single submitter | clinical testing | The p.H457D variant (also known as c.1369C>G), located in coding exon 11 of the LAMA4 gene, results from a C to G substitution at nucleotide position 1369. The histidine at codon 457 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is poorly 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. |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV001725122 | SCV001959996 | likely benign | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV001725122 | SCV001969632 | likely benign | not provided | no assertion criteria provided | clinical testing |