Submissions for variant NM_004525.3(LRP2):c.2933C>T (p.Thr978Met)

gnomAD frequency: 0.00322  dbSNP: rs114842875

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000885726	SCV001029191	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001133138	SCV001292825	benign	Donnai-Barrow syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Genome-Nilou Lab	RCV001133138	SCV002055121	benign	Donnai-Barrow syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001726361	SCV002556277	benign	not specified	2022-06-30	criteria provided, single submitter	clinical testing	Variant summary: LRP2 c.2933C>T (p.Thr978Met) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0037 in 250792 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 3 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. To our knowledge, no occurrence of c.2933C>T in individuals affected with Donnai Barrow Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000885726	SCV004147280	benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	LRP2: BS1, BS2
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000885726	SCV001926355	likely benign	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001726361	SCV001962773	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003930654	SCV004744537	benign	LRP2-related disorder	2019-05-13	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).