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NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) AND not specified

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 9, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003330518.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys)]

NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys)

Gene:
LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.2
Genomic location:
Preferred name:
NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys)
Other names:
NM_000527.5(LDLR):c.1720C>T
HGVS:
  • NC_000019.10:g.11116873C>T
  • NG_009060.1:g.32493C>T
  • NM_000527.5:c.1720C>TMANE SELECT
  • NM_001195798.2:c.1720C>T
  • NM_001195799.2:c.1597C>T
  • NM_001195800.2:c.1216C>T
  • NM_001195803.2:c.1339C>T
  • NP_000518.1:p.Arg574Cys
  • NP_000518.1:p.Arg574Cys
  • NP_001182727.1:p.Arg574Cys
  • NP_001182728.1:p.Arg533Cys
  • NP_001182729.1:p.Arg406Cys
  • NP_001182732.1:p.Arg447Cys
  • LRG_274t1:c.1720C>T
  • LRG_274:g.32493C>T
  • NC_000019.9:g.11227549C>T
  • NM_000527.4(LDLR):c.1720C>T
  • NM_000527.4:c.1720C>T
  • P01130:p.Arg574Cys
  • c.1720C>T
  • p.(Arg574Cys)
Protein change:
R406C
Links:
LDLR-LOVD, British Heart Foundation: LDLR_000232; UniProtKB: P01130#VAR_072851; dbSNP: rs185098634
NCBI 1000 Genomes Browser:
rs185098634
Molecular consequence:
  • NM_000527.5:c.1720C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195798.2:c.1720C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195799.2:c.1597C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195800.2:c.1216C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001195803.2:c.1339C>T - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
no known functional consequence - Comment(s)

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004038484Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Uncertain significance
(Aug 9, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Identification of recurrent and novel mutations in the LDL receptor gene in German patients with familial hypercholesterolemia.

Nauck MS, Köster W, Dörfer K, Eckes J, Scharnagl H, Gierens H, Nissen H, Nauck MA, Wieland H, März W.

Hum Mutat. 2001 Aug;18(2):165-6.

PubMed [citation]
PMID:
11462246

The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population.

Damgaard D, Larsen ML, Nissen PH, Jensen JM, Jensen HK, Soerensen VR, Jensen LG, Faergeman O.

Atherosclerosis. 2005 May;180(1):155-60. Epub 2005 Jan 12.

PubMed [citation]
PMID:
15823288
See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004038484.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Variant summary: LDLR c.1720C>T (p.Arg574Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251482 control chromosomes (gnomAD). c.1720C>T has been reported in the literature in many individuals affected with Hypercholesterolemia, primarily in settings of gene or multigene panel testing in large cohorts of patients and in some cases their relatives, but without strong documented evidence of segregation (e.g. Nauck_2001, Damgaard_2005, Bertolini_2013, Trinder_2020, Leren_2021, Noto_2022). These data suggest the variant may be associated with Familial Hypercholesterolemia but do not allow for unequivocal conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function in a high-throughput in vitro system and found no damaging effect of this variant (e.g. Thormaehlen_2015). Ten submitters, including the ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The variant has been classified as either pathogenic (n=1)/likely pathogenic (n=5) or VUS (n=4, including the ClinGen Expert Panel). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024