Submissions for variant NM_004525.3(LRP2):c.1973A>G (p.Tyr658Cys)

gnomAD frequency: 0.00248  dbSNP: rs111360923

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000301446	SCV000419185	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000885594	SCV001029053	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000885594	SCV001772747	uncertain significance	not provided	2023-03-26	criteria provided, single submitter	clinical testing	Observed in a child with sensorineural hearing loss, dysplastic bilateral vestibules, bilateral hypoplastic cochlea, and bilateral lateral and posterior semicircular canal aplasia in a published case report (Albazroun et al., 2018); however, no second LRP2 variant was reported and variants in other genes were also found; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Albazroun_2018_Case report)
Genome-Nilou Lab	RCV000301446	SCV002055700	likely benign	Donnai-Barrow syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021777	SCV004897466	likely benign	Inborn genetic diseases	2021-09-17	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	RCV003969954	SCV004779961	benign	LRP2-related disorder	2020-05-04	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).