ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.413C>G (p.Ser138Ter)

gnomAD frequency: 0.00001  dbSNP: rs755799528
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238345 SCV000294692 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Labcorp Genetics (formerly Invitae), Labcorp RCV002229687 SCV000627037 pathogenic Familial hypercholesterolemia 2022-05-20 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: 251208). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 22881376, 32331935). This variant is present in population databases (rs755799528, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Ser138*) 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 RCV004017542 SCV004847684 likely pathogenic Homozygous familial hypercholesterolemia 2019-04-16 criteria provided, single submitter clinical testing The p.Ser138X variant in LDLR has been reported in one individual with familial hypercholesterolemia (FH; Usifo 2012). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 251208) and has been identified in 0.007% (2/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. This nonsense variant leads to a premature termination codon at position 138, which is predicted to lead to a truncated or absent protein. Loss of function of the LDLR gene is an established disease mechanism in autosomal dominant FH. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PVS1, PM2.

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