ClinVar Miner

Submissions for variant NM_014646.2(LPIN2):c.1099G>A (p.Ala367Thr) (rs540544894)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000216428 SCV000279001 uncertain significance not provided 2017-09-28 criteria provided, single submitter clinical testing To our knowledge, the A367T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant. The variant is observed in 9/18868 (0.048%) alleles from individuals of East Asian background in the ExAC dataset (Lek et al., 2016). A367T 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, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000348256 SCV000408486 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.
Invitae RCV000348256 SCV000824364 uncertain significance Majeed syndrome 2019-08-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 367 of the LPIN2 protein (p.Ala367Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs540544894, ExAC 0.03%). This variant has not been reported in the literature in individuals with LPIN2-related disease. ClinVar contains an entry for this variant (Variation ID: 234331). 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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