Submissions for variant NM_004525.3(LRP2):c.13921A>T (p.Thr4641Ser)

gnomAD frequency: 0.00123  dbSNP: rs79179577

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000332291	SCV000419008	likely benign	Donnai-Barrow 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000937936	SCV001083731	likely benign	not provided	2024-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000937936	SCV001754290	uncertain significance	not provided	2022-05-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV000332291	SCV002054518	likely benign	Donnai-Barrow syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003168500	SCV003871199	likely benign	Inborn genetic diseases	2023-01-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003922426	SCV004742302	likely benign	LRP2-related disorder	2022-04-07	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
New York Genome Center	RCV001254976	SCV001431064	uncertain significance	Global developmental delay	2019-12-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000937936	SCV001549107	uncertain significance	not provided		no assertion criteria provided	clinical testing	The LRP2 p.T4641S variant was not identified in the literature but was identified in dbSNP (ID: rs79179577) and ClinVar (classified as likely benign by Invitae and Illumina; and as uncertain significance by New York Genome Center). The variant was identified in control databases in 103 of 282640 chromosomes at a frequency of 0.0003644, and was observed at the highest frequency in the African population in 97 of 24968 chromosomes (freq: 0.003885) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.T4641 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.