ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.232C>T (p.Arg78Cys) (rs370860696)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000211670 SCV000294541 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Color Health, Inc RCV001181333 SCV001346457 uncertain significance Familial hypercholesterolemia 2020-07-30 criteria provided, single submitter clinical testing This missense variant (also known as p.Arg57Cys in the mature protein) replaces arginine with cysteine at codon 78 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9259195, 9664576, 24956927, 32522009). This variant has been identified in 8/282882 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001181333 SCV001416327 uncertain significance Familial hypercholesterolemia 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 78 of the LDLR protein (p.Arg78Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs370860696, ExAC 0.01%). This variant has been observed in individuals affected with familial hypercholesterolemia (PMID: 22910581, 9237502, 9664576, 22883975, 24956927, 9259195). This variant is also known as R57C in the literature. ClinVar contains an entry for this variant (Variation ID: 161289). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CSER _CC_NCGL, University of Washington RCV000148596 SCV000190311 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Cardiovascular Genetics Laboratory,PathWest Laboratory Medicine WA - Fiona Stanley Hospital RCV000211670 SCV000268543 pathogenic Familial hypercholesterolemia 1 2010-11-29 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001181333 SCV001422745 uncertain significance Familial hypercholesterolemia 2020-01-22 no assertion criteria provided curation The p.Arg78Cys variant in LDLR has been reported in at least 9 individuals with familial hypercholesterolemia (PMID: 9259195, 28502495, 11845603, 9664576, 22883975, 24956927, 27680772) and has been Identified in 0.01002% (2/19952) of East Asian chromosomes, and at lower frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs370860696). This variant has also been reported in ClinVar (VariationID: 161289) as likely pathogenic by the British Heart Foundation, pathogenic by Fiona Stanley Hospital, and as a VUS by the University of Washington Medical Center. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_moderate (Richards 2015).
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354269 SCV001548842 uncertain significance not provided no assertion criteria provided clinical testing The LDLR p.Arg78Cys variant was identified in 2 of 1606 proband chromosomes (frequency: 0.001) from individuals with familial hypercholesterolemia (FH) (Callis_1998_PMID:9664576; Day_1997_PMID:9259195). The variant was also identified in 1 of 232 individuals from a Scottish cohort with moderately high total cholesterol despite cholesterol-lowering therapy but was not identified in 192 controls or 193 individuals with high cholesterol (Norsworthy_2014_PMID:24956927). In a family with FH, the p.A78C variant was identified in the mother with classical heterozygous FH who also carried a deletion of exons 2-5 of the LDLR gene. The father carried the exon 2-5 deletion as well as another intronic LDLR variant and also presented with classical heterozygous FH. The child was homozygous for the exon 2-5 deletion and presented with classical homozygous FH, suggesting that the exon 2-5 deletion was the cause of disease in this family and that the p.A78C variant likely does not contribute to disease in the mother (Jelassi_2012_PMID:22910581). The variant was identified in dbSNP (ID: rs370860696), LOVD 3.0 and ClinVar (classified as a VUS by CSER_CC_NCGL; University of Washington Medical Center, likely pathogenic by LDLR-LOVD, British Heart Foundation and pathogenic by Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital). The variant was identified in control databases in 8 of 282882 chromosomes at a frequency of 0.000028 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 2 of 19952 chromosomes (freq: 0.0001), South Asian in 2 of 30616 chromosomes (freq: 0.000065), African in 1 of 24968 chromosomes (freq: 0.00004) and European (non-Finnish) in 3 of 129190 chromosomes (freq: 0.000023), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish) or Other populations. The p.Arg78 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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