ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.660del (p.Asp221fs)

dbSNP: rs875989905
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211699 SCV000294857 pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
Invitae RCV000824495 SCV000965394 pathogenic Familial hypercholesterolemia 2021-02-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 9678702, 11139254, 22883975, 11462246, 15556094). This variant is also known as P199fsX243, 657delC. ClinVar contains an entry for this variant (Variation ID: 226330). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asp221Thrfs*44) 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).
Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia RCV000211699 SCV001432618 pathogenic Hypercholesterolemia, familial, 1 2019-05-11 criteria provided, single submitter research
Ambry Genetics RCV002363057 SCV002664460 pathogenic Cardiovascular phenotype 2023-12-13 criteria provided, single submitter clinical testing The c.660delC (p.D221Tfs*44) alteration, located in exon 4 (coding exon 4) of the LDLR gene, consists of a deletion of one nucleotide at position 660, causing a translational frameshift with a predicted alternate stop codon after 44 amino acids. Frameshift alterations are typically deleterious in nature (Richards, 2015). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation (also described as c.657delC) has been reported in numerous familial hypercholesterolemia (FH) cohorts from a variety of ethnic backgrounds (Lee, 1998; Bochmann, 2001; Laurie, 2004; Bamimore, 2015; Hu, 2016). Based on the available evidence, this alteration is classified as pathogenic.
GeneDx RCV003235135 SCV003933319 pathogenic not provided 2022-12-14 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34037665, 9678702)
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211699 SCV000268575 pathogenic Hypercholesterolemia, familial, 1 2014-05-05 no assertion criteria provided clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000211699 SCV000606183 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Natera, Inc. RCV000824495 SCV002086377 pathogenic Familial hypercholesterolemia 2020-12-07 no assertion criteria provided clinical testing

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