ClinVar Miner

Submissions for variant NM_002294.2(LAMP2):c.472A>G (p.Thr158Ala) (rs138374063)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000547615 SCV000636864 uncertain significance Danon disease 2017-06-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 158 of the LAMP2 protein (p.Thr158Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs138374063, ExAC 0.01%) but has not been reported in the literature in individuals with a LAMP2-related disease. ClinVar contains an entry for this variant (Variation ID: 44429). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037419 SCV000061076 uncertain significance not specified 2012-07-06 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Thr158Ala varia nt in LAMP2 has been identified in 2/6727 European American chromosomes from a b road population by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS; dbSNP rs138374063). Threonine (Thr) at position 158 is not conserved in mammals or evolutionarily distant species and elephant carries an alanine (Ala; this variant), suggesting that this change may be tolerated. In addition, compu tational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impact the protein, though this informat ion is not predictive enough to rule out pathogenicity. In summary, the frequenc y of this variant and lack of amino acid conservation suggests that it may be mo re likely benign, but additional information is needed to fully assess its clini cal significance.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000675449 SCV000801131 uncertain significance not provided 2017-11-13 no assertion criteria provided clinical testing

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