ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.48C>A (p.Leu16=)

gnomAD frequency: 0.00001  dbSNP: rs565675103
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000238433 SCV005375294 likely benign Hypercholesterolemia, familial, 1 2023-11-07 reviewed by expert panel curation The NM_000527.5 (LDLR):c.48C>A (p.Leu16=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP4, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF=0.00006 in Latino population in gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in 1 index case with possible FH by Simon Broome criteria, after alternative causes of high cholesterol were excluded, from PMID 7635461 (Ekstrom et al., 1995), Sweden. BP4: Variant is synonymous and splicing evaluation is required. Functional data on splicing is not available. MES: A) Not on limits. B) Not on limits. Variant is not predicted to alter splicing. SpliceAI did not predict alternative splicing (? score=0). BP7 met: Variant is synonymous and meets BP4. This variant has 2 supporting evidence codes (BP4, BP7) towards Benign, enough to classify as Likely Benign, and only PM2 and PP4 evidence codes towards Pathogenic, not enough for Likely Pathogenic, so we are confident in classifying this variant as Likely Benign.
LDLR-LOVD, British Heart Foundation RCV000238433 SCV000294424 benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Fundacion Hipercolesterolemia Familiar RCV000238433 SCV000607407 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Ambry Genetics RCV002338777 SCV002635798 likely benign Cardiovascular phenotype 2023-08-08 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV003581593 SCV004298007 likely benign Familial hypercholesterolemia 2023-11-10 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000238433 SCV004820105 likely benign Hypercholesterolemia, familial, 1 2023-12-01 criteria provided, single submitter clinical testing

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