Submissions for variant NM_000527.5(LDLR):c.2546C>A (p.Ser849Ter)

dbSNP: rs377437226

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238059	SCV001960946	likely pathogenic	Hypercholesterolemia, familial, 1	2021-06-22	reviewed by expert panel	curation	NM_000527.5(LDLR):c.2546C>A (p.Ser849Ter) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PVS1_Moderate, PP4 and PS4_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - No population data was found for this allele in gnomAD (gnomAD v2.1.1). PVS1_moderate - Variant is nonsense after amino acid 830 (NM_000527.5:p.Lys830). PP4 - Variant meets PM2. Variant identified in 2 index FH cases (1 case from Color laboratory with Simon-Broome criteria; 1 case with Simon-Broome criteria published in PMID: 26892515). PS4_supporting - Variant meets PM2. Variant identified in 2 index cases (1 case from Color laboratory with Simon-Broome criteria; 1 case with Simon-Broome criteria published in PMID: 26892515).
LDLR-LOVD, British Heart Foundation	RCV000238059	SCV000296029	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Invitae	RCV001178793	SCV000830787	pathogenic	Familial hypercholesterolemia	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser849*) in the LDLR gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 12 amino acid(s) of the LDLR protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 11933210, 26892515). ClinVar contains an entry for this variant (Variation ID: 252350). This variant disrupts a region of the LDLR protein in which other variant(s) (Deletion (Exon 18)) have been determined to be pathogenic (PMID: 16159606; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001178793	SCV001343308	likely pathogenic	Familial hypercholesterolemia	2020-04-08	criteria provided, single submitter	clinical testing	This variant deletes the last 12 amino acids from C-terminal cytoplasmic domain of the LDLR protein. This variant may not result in nonsense mediated mRNA decay but is expected to disrupt a part of the C-terminal cytoplasmic domain, which is required for internalization of the LDLR protein (PMID: 22509010, 2088165). Although functional studies have not been reported, this variant is likely to have a deleterious impact on the LDLR function. This variant and a different variant with the same protein effect (c.2546del) have been observed in two individuals affected with familial hypercholesterolemia (PMID: 26892515, 11933210). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001178793	SCV001434876	likely pathogenic	Familial hypercholesterolemia	2018-10-12	criteria provided, single submitter	clinical testing	The c.2546C>A (p.Ser849*) variant in the LDLR gene is predicted to introduce a premature translation termination codon. This variant has not been reported in general population databases. Therefore, this c.2546C>A (p.Ser849*) variant is classified as likely pathogenic.
MGZ Medical Genetics Center	RCV000238059	SCV002580138	likely pathogenic	Hypercholesterolemia, familial, 1	2022-06-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000238059	SCV003831243	likely pathogenic	Hypercholesterolemia, familial, 1	2022-07-27	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238059	SCV000606666	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV001178793	SCV002086884	likely pathogenic	Familial hypercholesterolemia	2020-08-13	no assertion criteria provided	clinical testing