Submissions for variant NM_002294.3(LAMP2):c.661G>A (p.Gly221Arg) (rs145169006)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000037424	SCV000061081	likely benign	not specified	2015-05-26	criteria provided, single submitter	clinical testing	p.Gly221Arg in LAMP2: This variant is not expected to have clinical significance because it has been identified in 0.2% (84/47999) of European chromosomes, incl uding 30 males, by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org/; dbSNP rs145169006).
GeneDx	RCV000037424	SCV000207890	likely benign	not specified	2017-12-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000465775	SCV000560067	likely benign	Danon disease	2019-12-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000755557	SCV000604090	benign	not provided	2017-10-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617835	SCV000736900	benign	Cardiovascular phenotype	2017-06-15	criteria provided, single submitter	clinical testing	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000037424	SCV000740589	likely benign	not specified	2016-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000718230	SCV000849092	benign	History of neurodevelopmental disorder	2017-06-15	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego	RCV000853049	SCV000995807	benign	Cardiomyopathy	2019-05-14	criteria provided, single submitter	clinical testing
Human Genetics Laboratory,State University of Rio de Janeiro	RCV001089470	SCV000996528	uncertain significance	Intellectual disability	2020-04-07	criteria provided, single submitter	research
Mendelics	RCV000465775	SCV001142004	likely benign	Danon disease	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000465775	SCV001330759	benign	Danon disease	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Integrated Genetics/Laboratory Corporation of America	RCV000037424	SCV001362570	benign	not specified	2019-03-04	criteria provided, single submitter	clinical testing	Variant summary: LAMP2 c.661G>A (p.Gly221Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 200310 control chromosomes in the gnomAD database, including 1 homozygote and 95 hemizygotes. The observed variant frequency is approximately 120 fold of the estimated maximal expected allele frequency for a pathogenic variant in LAMP2 causing Cardiomyopathy phenotype (1.3e-05), strongly suggesting that the variant is benign. The variant c.661G>A has been reported in the literature in patients with dilated (DCM) or hypertrophic (HCM) cardiomyopathies, however without evidence for causality (e.g. Mook 2013, Cecconi 2016, Mademont-Soler 2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (2x)/likely benign(4x). Based on the evidence outlined above, the variant was classified as benign.
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen	RCV000465775	SCV000734734	likely benign	Danon disease		no assertion criteria provided	clinical testing