BS2, BP4

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.

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.

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.

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.

LAMP2: BP4, BS2