Submissions for variant NM_000527.5(LDLR):c.922G>T (p.Glu308Ter)

dbSNP: rs879254721

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000777500	SCV000913362	pathogenic	Familial hypercholesterolemia	2018-02-07	criteria provided, single submitter	clinical testing	Pathogenic variant based on current evidence: This variant changes one nucleotide in exon 8 of the LDLR mRNA (c.922G>T). This creates a premature translational stop signal (p.Glu308*) and is expected to result in an absent or non-functional protein product. Truncating variants in LDLR are known to be pathogenic (PMID: 20809525). This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. Based on available evidence, this variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017734	SCV004848164	pathogenic	Homozygous familial hypercholesterolemia	2018-02-08	criteria provided, single submitter	clinical testing	The p.Glu308X variant in LDLR has not been reported in individual with familial hypercholesterolemia or large population studies. This nonsense variant leads to a premature termination codon at position 308, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in individuals with familial hypercholesterolemia. In summary, this variant meets criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon the predicted impact to the protein and absence from controls. ACMG/AMP Criteria applied: PVS1; PM2.