NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 21, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000486101.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys)]

NM_000527.5(LDLR):c.1897C>T (p.Arg633Cys)

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.1897C>T (p.Arg633Cys)

Other names:

NP_000518.1:p.R633C

HGVS:

NC_000019.10:g.11120143C>T
NG_009060.1:g.35763C>T
NM_000527.5:c.1897C>TMANE SELECT
NM_001195798.2:c.1897C>T
NM_001195799.2:c.1774C>T
NM_001195800.2:c.1393C>T
NM_001195803.2:c.1516C>T
NP_000518.1:p.Arg633Cys
NP_000518.1:p.Arg633Cys
NP_001182727.1:p.Arg633Cys
NP_001182728.1:p.Arg592Cys
NP_001182729.1:p.Arg465Cys
NP_001182732.1:p.Arg506Cys
LRG_274t1:c.1897C>T
LRG_274:g.35763C>T
LRG_274p1:p.Arg633Cys
NC_000019.9:g.11230819C>T
NM_000527.4:c.1897C>T
NM_000527.5:c.1897C>T
P01130:p.Arg633Cys
c.1897C>T

Protein change:

R465C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001544; UniProtKB: P01130#VAR_005405

Molecular consequence:

NM_000527.5:c.1897C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1897C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1774C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1393C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1516C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000567421	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 26, 2022)	germline	clinical testing	Citation Link,
SCV002502727	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 21, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9259195, 23375686, 32015373, 31491741, 30586733, 31447099, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000567421

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 26, 2022)

germline

clinical testing

Citation Link,

SCV002502727

AiLife Diagnostics, AiLife Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 21, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemia.

Day IN, Whittall RA, O'Dell SD, Haddad L, Bolla MK, Gudnason V, Humphries SE.

Hum Mutat. 1997;10(2):116-27.

PubMed [citation]

PMID:: 9259195

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]

PMID:: 23375686

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000567421.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect as Western blotting showed decreased expression and reduced LDL uptake suggesting a negative effect on LDLR receptor recycling (Galicia-Garcia et al., 2020); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#226379; ClinVar); Also reported as R612C due to alternate nomenclature; This variant is associated with the following publications: (PMID: 28349888, 27680772, 9259195, 15241806, 27578128, 28235710, 19843101, 16159606, 20538126, 23375686, 19446849, 18700895, 17539906, 22698793, 21376320, 19538517, 17094996, 32015373, 31447099, 31491741, 30586733, 31589614, 34037665, 33087929, 32041611, 32719484)

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

From AiLife Diagnostics, AiLife Diagnostics, SCV002502727.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (7)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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