Submissions for variant NM_004525.3(LRP2):c.12379C>A (p.Arg4127Ser)

gnomAD frequency: 0.00217  dbSNP: rs148356370

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000283599	SCV000419033	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	RCV000952825	SCV001099356	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000952825	SCV001813622	likely benign	not provided	2020-08-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25158045)
Genome-Nilou Lab	RCV000283599	SCV002054200	benign	Donnai-Barrow syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222489	SCV002500388	benign	not specified	2022-03-14	criteria provided, single submitter	clinical testing	Variant summary: LRP2 c.12379C>A (p.Arg4127Ser) results in a non-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. The variant allele was found at a frequency of 0.0031 in 251338 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 2.8 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. Four 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/likely benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000952825	SCV004042092	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	LRP2: BP4, BS2
PreventionGenetics, part of Exact Sciences	RCV003940332	SCV004752478	likely benign	LRP2-related condition	2020-01-23	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).