Submissions for variant NM_004525.3(LRP2):c.2540G>A (p.Arg847His)

gnomAD frequency: 0.00006  dbSNP: rs537125368

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000845028	SCV001289121	uncertain significance	Donnai-Barrow syndrome	2018-01-15	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001858450	SCV002286502	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 847 of the LRP2 protein (p.Arg847His). This variant is present in population databases (rs537125368, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with LRP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 684510). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000845028	SCV002781726	uncertain significance	Donnai-Barrow syndrome	2022-03-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002536158	SCV003751146	uncertain significance	Inborn genetic diseases	2022-10-12	criteria provided, single submitter	clinical testing	The c.2540G>A (p.R847H) alteration is located in exon 18 (coding exon 18) of the LRP2 gene. This alteration results from a G to A substitution at nucleotide position 2540, causing the arginine (R) at amino acid position 847 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV001858450	SCV004024062	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
GenomeConnect, ClinGen	RCV000845028	SCV000986863	not provided	Donnai-Barrow syndrome		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 09/06/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.