Submissions for variant NM_001375808.2(LPIN2):c.2171A>G (p.Asn724Ser)

gnomAD frequency: 0.00001  dbSNP: rs140915714

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000218824	SCV000279013	uncertain significance	not provided	2016-08-05	criteria provided, single submitter	clinical testing	The c.2171 A>G variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The c.2171 A>G variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.2171 A>G (p.Asn724Ser) variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this variant is predicted to create a strong cryptic splice donor site and occurs at a position that is conserved across species. 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 mutation or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001060981	SCV001225703	uncertain significance	Majeed syndrome	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 724 of the LPIN2 protein (p.Asn724Ser). This variant is present in population databases (rs140915714, gnomAD 0.01%). 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: 234341). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002262819	SCV002543552	uncertain significance	Autoinflammatory syndrome	2020-04-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001060981	SCV003817039	uncertain significance	Majeed syndrome	2021-10-19	criteria provided, single submitter	clinical testing