ClinVar Miner

Submissions for variant NM_004525.3(LRP2):c.13921A>T (p.Thr4641Ser)

gnomAD frequency: 0.00123  dbSNP: rs79179577
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000332291 SCV000419008 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 RCV000937936 SCV001083731 likely benign not provided 2024-01-27 criteria provided, single submitter clinical testing
GeneDx RCV000937936 SCV001754290 uncertain significance not provided 2022-05-23 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab RCV000332291 SCV002054518 likely benign Donnai-Barrow syndrome 2021-07-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV003168500 SCV003871199 likely benign Inborn genetic diseases 2023-01-10 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.
New York Genome Center RCV001254976 SCV001431064 uncertain significance Global developmental delay 2019-12-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000937936 SCV001549107 uncertain significance not provided no assertion criteria provided clinical testing The LRP2 p.T4641S variant was not identified in the literature but was identified in dbSNP (ID: rs79179577) and ClinVar (classified as likely benign by Invitae and Illumina; and as uncertain significance by New York Genome Center). The variant was identified in control databases in 103 of 282640 chromosomes at a frequency of 0.0003644, and was observed at the highest frequency in the African population in 97 of 24968 chromosomes (freq: 0.003885) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.T4641 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) 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 (Splice AI exome) 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.

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