Submissions for variant NM_001105206.3(LAMA4):c.2569G>A (p.Ala857Thr)

gnomAD frequency: 0.00006  dbSNP: rs144123257

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154738	SCV000204418	likely benign	not specified	2014-02-07	criteria provided, single submitter	clinical testing	Ala850Thr in exon 20 of LAMA4: This variant has been identified in 2/8600 Europe an American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS/; dbSNP rs144123257). This variant is not expected to have cli nical significance due to a lack of conservation across species, including mamma ls. Of note, 27 species have a threonine (Thr) at this position despite high nea rby amino acid conservation. Ala850Thr in exon 20 of LAMA4 (rs144123257; allel e frequency = 2/8600) **
Ambry Genetics	RCV000617876	SCV000736734	likely benign	Cardiovascular phenotype	2019-08-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000605608	SCV000744217	likely benign	Dilated cardiomyopathy 1JJ	2017-05-31	criteria provided, single submitter	clinical testing
Invitae	RCV000605608	SCV002140796	uncertain significance	Dilated cardiomyopathy 1JJ	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 850 of the LAMA4 protein (p.Ala850Thr). This variant is present in population databases (rs144123257, gnomAD 0.01%). 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: 178053). 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 threonine 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000605608	SCV000734440	likely benign	Dilated cardiomyopathy 1JJ		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001699210	SCV001922861	likely benign	not provided		no assertion criteria provided	clinical testing