ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.664_681dup18 (p.Asp227_Glu228insCysLysAspLysSerAsp)

dbSNP: rs387906306
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001201377 SCV000285033 pathogenic Familial hypercholesterolemia 2024-01-25 criteria provided, single submitter clinical testing This variant, c.664_681dup, results in the insertion of 6 amino acid(s) of the LDLR protein (p.Cys222_Asp227dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs387906306, gnomAD 0.0009%). This variant has been observed in individual(s) with familial hypercholesterolemia (PMID: 7581403, 7649546, 10978268, 20145306). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as p.201-206dup and CKDKSD206–207ins. ClinVar contains an entry for this variant (Variation ID: 3733). For these reasons, this variant has been classified as Pathogenic.
LDLR-LOVD, British Heart Foundation RCV000003931 SCV000294867 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II RCV000003931 SCV001653599 likely pathogenic Hypercholesterolemia, familial, 1 2021-05-24 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV003457636 SCV004185153 likely pathogenic not provided 2023-11-01 criteria provided, single submitter clinical testing LDLR: PM2, PM4, PS2:Moderate, PS4:Moderate
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000003931 SCV004848338 likely pathogenic Hypercholesterolemia, familial, 1 2020-04-16 criteria provided, single submitter clinical testing The p.Cys222_Asp227dup variant in LDLR (also known as FH Padua-4l) has been reported in 5 families with hypercholesterolemia, occured de novo in 1 of these individuals, and segregated with disease in at least 1 affected relative (Bertolini 2000, Chmara 2010, Giesel 1995, Kotze 1995, Pavanello 2019). This variant has also been identified in 1/12968 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID 3733). This variant is an insertion of 6 amino acids at position 222 and is not predicted to alter the protein reading-frame. 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 hypercholesterolemia. ACMG/AMP Criteria applied: PM6, PM2, PS4_Moderate.
OMIM RCV000003931 SCV000024096 pathogenic Hypercholesterolemia, familial, 1 1995-01-01 no assertion criteria provided literature only
Natera, Inc. RCV001201377 SCV002086379 pathogenic Familial hypercholesterolemia 2021-05-07 no assertion criteria provided clinical testing

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