NM_000527.5(LDLR):c.769C>T (p.Arg257Trp) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 18, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001800605.4

Allele description [Variation Report for NM_000527.5(LDLR):c.769C>T (p.Arg257Trp)]

NM_000527.5(LDLR):c.769C>T (p.Arg257Trp)

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.769C>T (p.Arg257Trp)

HGVS:

NC_000019.10:g.11106639C>T
NG_009060.1:g.22259C>T
NM_000527.5:c.769C>TMANE SELECT
NM_001195798.2:c.769C>T
NM_001195799.2:c.646C>T
NM_001195800.2:c.314-753C>T
NM_001195803.2:c.388C>T
NP_000518.1:p.Arg257Trp
NP_000518.1:p.Arg257Trp
NP_001182727.1:p.Arg257Trp
NP_001182728.1:p.Arg216Trp
NP_001182732.1:p.Arg130Trp
LRG_274t1:c.769C>T
LRG_274:g.22259C>T
LRG_274p1:p.Arg257Trp
NC_000019.9:g.11217315C>T
NM_000527.4:c.769C>T
P01130:p.Arg257Trp
c.769C>T

Protein change:

R130W

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000115; UniProtKB: P01130#VAR_072836

Molecular consequence:

NM_001195800.2:c.314-753C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.769C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.769C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.646C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.388C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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Nucleotide
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Nucleotide
BioAssay by Target (List) for Gene (Select 20289) (3)
PubChem BioAssay
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Nucleotide
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gi|223673671|gb|ACN12896.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002047051	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (May 13, 2021)	unknown	clinical testing	PubMed (24) [See all records that cite these PMIDs] 32759540, 32719484, 32041611, 31345425, 30795984, 30592178, 30526649, 30400955, 30293936, 29353225, 26690388, 26343872, 25962062, 25545329, 25461735, 22353362, 20538126, 19318025, 18325082, 16250003, 11933210, 11462246, 29399563, 26467025
SCV003844390	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jun 18, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25545329, 30795984, 33994402, 34456200 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002047051

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(May 13, 2021)

unknown

clinical testing

PubMed (24)
[See all records that cite these PMIDs]

SCV003844390

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jun 18, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia.

Wang H, Yang H, Liu Z, Cui K, Zhang Y, Zhang Y, Zhao K, Yin K, Li W, Zhou Z.

J Atheroscler Thromb. 2020 Dec 1;27(12):1288-1298. doi: 10.5551/jat.54593. Epub 2020 Aug 6.

PubMed [citation]

PMID:: 32759540
PMCID:: PMC7840166

Population genetic screening efficiently identifies carriers of autosomal dominant diseases.

Grzymski JJ, Elhanan G, Morales Rosado JA, Smith E, Schlauch KA, Read R, Rowan C, Slotnick N, Dabe S, Metcalf WJ, Lipp B, Reed H, Sharma L, Levin E, Kao J, Rashkin M, Bowes J, Dunaway K, Slonim A, Washington N, Ferber M, Bolze A, et al.

Nat Med. 2020 Aug;26(8):1235-1239. doi: 10.1038/s41591-020-0982-5. Epub 2020 Jul 27.

PubMed [citation]

PMID:: 32719484

See all PubMed Citations (26)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002047051.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (24)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003844390.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: LDLR c.769C>T (p.Arg257Trp) 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 9.5e-05 in 251486 control chromosomes, predominantly at a frequency of 0.00098 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (9.5e-05 vs 0.0013), allowing no conclusion about variant significance. c.769C>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia without strong evidence of causality (e.g. Luirink_2019, Huang_2022, Kim_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Etxebarria_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25545329, 30795984, 34456200, 33994402). ClinVar contains an entry for this variant (Variation ID: 251446). Based on the evidence outlined above, the variant was classified as likely benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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