Submissions for variant NM_001375808.2(LPIN2):c.2671G>A (p.Asp891Asn)

gnomAD frequency: 0.00034  dbSNP: rs200648652

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000395862	SCV000408467	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	RCV000480316	SCV000565115	uncertain significance	not provided	2017-06-22	criteria provided, single submitter	clinical testing	To our knowledge, the D891N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant. The D891N variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. It is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000395862	SCV000743504	likely benign	Majeed syndrome	2014-10-09	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000395862	SCV000744775	likely benign	Majeed syndrome	2017-01-04	criteria provided, single submitter	clinical testing
Invitae	RCV000395862	SCV000766472	uncertain significance	Majeed syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 891 of the LPIN2 protein (p.Asp891Asn). This variant is present in population databases (rs200648652, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with LPIN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 326632). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LPIN2 protein function. 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.
Blueprint Genetics	RCV000480316	SCV000927191	uncertain significance	not provided	2017-03-06	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002263038	SCV002543576	uncertain significance	Autoinflammatory syndrome	2021-08-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000395862	SCV003817036	uncertain significance	Majeed syndrome	2022-12-21	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000480316	SCV004224456	uncertain significance	not provided	2022-04-13	criteria provided, single submitter	clinical testing	BP4
PreventionGenetics, part of Exact Sciences	RCV003950114	SCV004763682	uncertain significance	LPIN2-related disorder	2024-01-16	criteria provided, single submitter	clinical testing	The LPIN2 c.2671G>A variant is predicted to result in the amino acid substitution p.Asp891Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.060% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GenomeConnect, ClinGen	RCV000395862	SCV000840196	not provided	Majeed syndrome		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.