Submissions for variant NM_004525.3(LRP2):c.6130G>A (p.Ala2044Thr)

gnomAD frequency: 0.00021  dbSNP: rs142266106

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000384646	SCV000419115	uncertain significance	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, 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	RCV000936176	SCV001081939	likely benign	not provided	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000936176	SCV001768371	uncertain significance	not provided	2020-01-09	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV000384646	SCV002055269	uncertain significance	Donnai-Barrow syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002521322	SCV003679136	likely benign	Inborn genetic diseases	2022-05-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV003910283	SCV004724379	likely benign	LRP2-related condition	2019-11-06	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000936176	SCV001549012	uncertain significance	not provided		no assertion criteria provided	clinical testing	The LRP2 p.Ala2044Thr variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs142266106) and ClinVar (classified as uncertain significance by Illumina for Donnai-Barrow Syndrome). The variant was identified in control databases in 83 of 282632 chromosomes at a frequency of 0.0002937 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 58 of 10356 chromosomes (freq: 0.005601), Other in 3 of 7216 chromosomes (freq: 0.000416), East Asian in 5 of 19946 chromosomes (freq: 0.000251), African in 5 of 24960 chromosomes (freq: 0.0002), South Asian in 3 of 30614 chromosomes (freq: 0.000098) and European (non-Finnish) in 9 of 129018 chromosomes (freq: 0.00007), but was not observed in the Latino or European (Finnish) populations. The p.Ala2044 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) 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 (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.