Submissions for variant NM_004525.3(LRP2):c.13803G>A (p.Met4601Ile)

gnomAD frequency: 0.00790  dbSNP: rs34564141

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000389214	SCV000419009	benign	Donnai-Barrow 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000953680	SCV001100261	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000389214	SCV002055922	benign	Donnai-Barrow syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844127	SCV002103757	benign	not specified	2022-02-23	criteria provided, single submitter	clinical testing	Variant summary: LRP2 c.13803G>A (p.Met4601Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0071 in 251230 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 6.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in LRP2 causing Donnai Barrow Syndrome phenotype (0.0011), strongly suggesting that the variant is benign. Although it appears in the literature, to our knowledge, no penetrant association of c.13803G>A in individuals affected with Donnai Barrow Syndrome and no supporting experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000953680	SCV004147228	benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	LRP2: BP4, BS1, BS2
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000953680	SCV001798125	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000953680	SCV001969633	likely benign	not provided		no assertion criteria provided	clinical testing