Submissions for variant NM_002294.3(LAMP2):c.586A>T (p.Thr196Ser)

gnomAD frequency: 0.00039  dbSNP: rs138991195

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037422	SCV000061079	likely benign	not specified	2014-12-17	criteria provided, single submitter	clinical testing	p.Thr196Ser in exon 5 of LAMP2: This variant has been reported in 2 males with a ccessory atrioventricular connections (Esposito 2009). Although it changes an a mino acid it is not expected to cause disease on its own for the following reaso ns: LAMP2 related disease is caused by a loss of function. Pathogenic missense variants are exceedingly rare (and those that have been reported lead to a loss of function by disrupting splicing). In addition, the Thr196Ser variant is prese nt at low frequency in large population data sets (30/67686 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org) and has been reported in at least 2 apparently healthy males (Esposito 2009). Our l aboratory has detected this variant in a 46 year old female with DCM as well as her reportedly unaffected 72 year old mother and two males with isolated HCM (72 and 63 years old). In summary, it is possible that this variant contributes to disease but it is likely benign on its own.
GeneDx	RCV000037422	SCV000207901	likely benign	not specified	2018-02-28	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.
Eurofins Ntd Llc (ga)	RCV000726564	SCV000345557	uncertain significance	not provided	2016-08-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083515	SCV000636866	benign	Danon disease	2025-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619957	SCV000736984	likely benign	Cardiovascular phenotype	2017-10-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000037422	SCV000740588	likely benign	not specified	2016-09-14	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000853431	SCV000996342	likely benign	Hypertrophic cardiomyopathy	2017-03-21	criteria provided, single submitter	research	The LAMP2 Thr196Ser variant has been previously reported in DCM (Pugh TJ, et al., 2014), a compound heterozygous case of mild Danon Disease (Cetin H, et al., 2016), 2 patients with accessory atrioventicular connections and in 2 male controls (Esposito G, et al., 2009). The LAMP2 Thr196Ser variant is found in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at an allele frequency >0.0002, which higher then expected for an inherited heart disease. We have identified the LAMP2 Thr196Ser variant in a male HCM proband who has a family history of disease (segregation not possible). This proband also carries a second variant; MYH6 Ser1414Phe. Computational tools are conflicting: SIFT and PolyPhen-2 predict LAMP2 Thr196Ser to be "deleterious" and "probably damaging", however MutationTaster predicts this variant to be a "polymorphism". In summary, the variant has been identified in controls and is seen at a high frequency in population databases, therefore we classify the LAMP2 Thr196Ser as "likely benign". Although it is unlikely that this variant causes disease on it's own, it's role as modifier can not be excluded.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798113	SCV002043171	likely benign	Cardiomyopathy	2023-06-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726564	SCV004165446	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	LAMP2: BP4, BS2
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000726564	SCV001741992	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000726564	SCV001924470	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000726564	SCV001929863	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000726564	SCV001959696	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000726564	SCV001965882	likely benign	not provided		no assertion criteria provided	clinical testing