Submissions for variant NM_002334.4(LRP4):c.2609G>A (p.Gly870Asp)

gnomAD frequency: 0.00001  dbSNP: rs776260999

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001104447	SCV001261313	uncertain significance	Cenani-Lenz syndactyly 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, 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	RCV001345966	SCV001540121	uncertain significance	Cenani-Lenz syndactyly syndrome; Sclerosteosis 2; Congenital myasthenic syndrome 17	2022-06-20	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 870 of the LRP4 protein (p.Gly870Asp). This variant is present in population databases (rs776260999, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with LRP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 878116). 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	RCV001345966	SCV002788310	uncertain significance	Cenani-Lenz syndactyly syndrome; Sclerosteosis 2; Congenital myasthenic syndrome 17	2021-10-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002558044	SCV003537055	uncertain significance	Inborn genetic diseases	2021-06-18	criteria provided, single submitter	clinical testing	The c.2609G>A (p.G870D) alteration is located in exon 19 (coding exon 19) of the LRP4 gene. This alteration results from a G to A substitution at nucleotide position 2609, causing the glycine (G) at amino acid position 870 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.