Submissions for variant NM_000527.5(LDLR):c.233del (p.Arg78fs)

dbSNP: rs1057516129

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Robarts Research Institute, Western University	RCV000408851	SCV000484802	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000408851	SCV001653584	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002523841	SCV003442659	pathogenic	Familial hypercholesterolemia	2022-03-13	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 369866). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg78Leufs*128) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017599	SCV004848002	pathogenic	Homozygous familial hypercholesterolemia	2016-06-14	criteria provided, single submitter	clinical testing	This p.Arg78Leufs variant in LDLR has not been previously reported in individuals with familial hypercholesterolemia or in large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 78 and leads to a premature termination codon 128 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of LDLR function is an established disease mechanism in familial hypercholesterolemia. In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia based on predicted impact to the protein and absence from the general population.
Ambry Genetics	RCV004629206	SCV005136006	pathogenic	Cardiovascular phenotype	2024-03-25	criteria provided, single submitter	clinical testing	The c.233delG pathogenic mutation, located in coding exon 3 of the LDLR gene, results from a deletion of one nucleotide at nucleotide position 233, causing a translational frameshift with a predicted alternate stop codon (p.R78Lfs*128). This variant has been reported in a whole exome sequencing cohort and a familial hypercholesterolemia (FH) cohort (Di Taranto MD et al. Clin Genet, 2021 Nov;100:529-541; Dewey FE et al. Science, 2016 Dec;354:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002523841	SCV005202241	pathogenic	Familial hypercholesterolemia	2024-07-30	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.233delG (p.Arg78LeufsX128) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251492 control chromosomes. c.233delG has been reported in the literature in at-least one individual affected with Familial Hypercholesterolemia (example: Wang_2016). The following publication has been ascertained in the context of this evaluation (PMID: 27765764). ClinVar contains an entry for this variant (Variation ID: 369866). Based on the evidence outlined above, the variant was classified as pathogenic.