Submissions for variant NM_000527.5(LDLR):c.920A>G (p.Asp307Gly)

dbSNP: rs1555803908

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Iberoamerican FH Network	RCV000627179	SCV000748090	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001227018	SCV001399353	pathogenic	Familial hypercholesterolemia	2024-09-14	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 307 of the LDLR protein (p.Asp307Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 19717150, 28502510, 30710474, 34037665). This variant is also known as Asp286Gly (D286G). ClinVar contains an entry for this variant (Variation ID: 523725). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Asp307 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 12436241, 17094996, 28965616), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001227018	SCV004028788	pathogenic	Familial hypercholesterolemia	2023-07-25	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.920A>G (p.Asp307Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251216 control chromosomes (gnomAD). c.920A>G has been reported in the literature in many heterozygous individuals affected with Familial Hypercholesterolemia (FH; e.g., Junyent_2008, Junyent_2010, Martin-Campos_2018, DiTaranto_2019, Sturm_2021, Marco-Benedi_2022, Zhan_2023 (preprint, no PMID)), as well as compound heterozygous and homozygous individuals affected with FH (e.g., Banaras_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28502510, 30710474, 18096825, 19717150, 34456049, 30293936, 34037665). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as likely pathogenic. Additionally, several different missense variants affecting the same codon, namely p.Asp307Asn, p.Asp307Glu, p.Asp307Ala, and p.Asp307His have all been reported in the literature in patients affected with familial hypercholesterolemia (PMIDs: 21310417, 33027386, 28965616, 12436241, 17094996). Based on the evidence outlined above, the variant was classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV000627179	SCV004101286	likely pathogenic	Hypercholesterolemia, familial, 1	2023-06-28	criteria provided, single submitter	clinical testing	The LDLR c.920A>G (p.Asp307Gly) missense variant lies in one of the ligand-binding domains. This variant has been reported in at least four unrelated individuals with familial hypercholesterolemia (PMID: 19717150; 30710474; 34037665; 34456049). The p.Asp307Gly variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Several other missense changes at the same amino acid residue have been reported in ClinVar and the literature in individuals with familial hypercholesterolemia (PMID: 21310417; 32706999). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the available evidence, the c.920A>G (p.Asp307Gly) variant is classified as likely pathogenic for familial hypercholesterolemia.
GeneDx	RCV004702208	SCV005201884	likely pathogenic	not provided	2023-09-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 19717150, 18096825, 28502510, 34037665, 30710474, 30293936, 34456049)
Mayo Clinic Laboratories, Mayo Clinic	RCV004702208	SCV005413306	pathogenic	not provided	2023-12-07	criteria provided, single submitter	clinical testing	PP3, PM2, PM3, PM5, PS4_moderate