ClinVar Miner

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

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Total submissions: 4
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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 RCV001000957 SCV000645175 likely benign Majeed syndrome 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000957 SCV001158056 uncertain significance Majeed syndrome 2018-12-25 criteria provided, single submitter clinical testing The LPIN2 c.446C>T; p.Pro140Leu variant (rs147615538) in an individual with myolysis (Michot 2012), but to our knowledge has not been described in an individual with Majeed syndrome. The variant is described in the ClinVar database (Variation ID: 378091) and in the general population with an allele frequency of 0.05% (130/282556 alleles including 1 homozygote). The proline at this position is weakly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. In support of this prediction, studies in yeast indicate this variant protein is able to function as wild type (Michot 2012). Although there are indications this variant may be benign, the clinical significance of this variant remains uncertain at this time. References: Michot C et al. Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia. J Inherit Metab Dis. 2012 Nov;35(6):1119-28.
Illumina Clinical Services Laboratory,Illumina RCV001000957 SCV001285574 uncertain significance Majeed syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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