ClinVar Miner

Submissions for variant NM_014646.2(LPIN2):c.446C>T (p.Pro149Leu) (rs147615538)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000436334 SCV000513503 uncertain significance not specified 2017-04-18 criteria provided, single submitter clinical testing The P149L variant has not been published in association with Majeed syndrome to our knowledge. The variant is observed in 58/66722 (0.087%) alleles from individuals of European background in the ExAC dataset (Lek et al., 2016). P149L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Functional studies have shown P149L performs similarly to the wild type allele in yeast complementation assays (Michot et al., 2012). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000542676 SCV000645175 uncertain significance Majeed syndrome 2017-07-10 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 149 of the LPIN2 protein (p.Pro149Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs147615538, ExAC 0.09%). This variant has been reported in the literature in an individual affected with rhabdomyolysis (PMID: 22481384). ClinVar contains an entry for this variant (Variation ID: 378091). Experimental studies in yeast have shown that this missense change does not affect LPIN2 function (PMID: 22481384). In summary, this variant has been reported in affected individuals and the general population, and had no impact on LPIN2 function in vitro. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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