ClinVar Miner

Submissions for variant NM_002294.3(LAMP2):c.586A>T (p.Thr196Ser) (rs138991195)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726564 SCV000345557 uncertain significance not provided 2016-08-25 criteria provided, single submitter clinical testing
Invitae RCV001083515 SCV000636866 benign Danon disease 2020-12-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619957 SCV000736984 likely benign Cardiovascular phenotype 2017-10-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification
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
Ambry Genetics RCV000721007 SCV000851891 likely benign History of neurodevelopmental disorder 2017-10-13 criteria provided, single submitter clinical testing Other strong data supporting benign classification
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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000726564 SCV001741992 likely benign not provided no assertion criteria provided clinical testing

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