ClinVar Miner

Submissions for variant NM_014646.2(LPIN2):c.1132C>T (p.Pro378Ser) (rs201678207)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000312207 SCV000408485 uncertain significance Majeed syndrome 2018-01-13 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.
GeneDx RCV000482609 SCV000565113 uncertain significance not provided 2018-01-31 criteria provided, single submitter clinical testing The P378S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is observed in 47/126708 (0.0371%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). P378S is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000312207 SCV000766474 uncertain significance Majeed syndrome 2019-10-19 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 378 of the LPIN2 protein (p.Pro378Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs201678207, ExAC 0.04%). This variant has not been reported in the literature in individuals with LPIN2-related disease. ClinVar contains an entry for this variant (Variation ID: 326646). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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