Submissions for variant NM_001375808.2(LPIN2):c.446C>T (p.Pro149Leu)

gnomAD frequency: 0.00038  dbSNP: rs147615538

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703462	SCV000513503	likely benign	not provided	2019-11-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22481384)
Invitae	RCV001000957	SCV000645175	likely benign	Majeed syndrome	2024-01-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001000957	SCV001158056	uncertain significance	Majeed syndrome	2020-02-03	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. This variant is reported in ClinVar (Variation ID: 378091) and. is found in the general population with an overall allele frequency of 0.05% (130/282556 alleles including 1 homozygote) in the Genome Aggregation Database. 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 Laboratory Services, 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263672	SCV002543582	uncertain significance	Autoinflammatory syndrome	2018-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001703462	SCV004010586	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	LPIN2: BP4, BS1