NM_000527.5(LDLR):c.313C>T (p.Pro105Ser) AND Hypercholesterolemia, familial, 1

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 13, 2023
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:: RCV000237815.3

Allele description [Variation Report for NM_000527.5(LDLR):c.313C>T (p.Pro105Ser)]

NM_000527.5(LDLR):c.313C>T (p.Pro105Ser)

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.313C>T (p.Pro105Ser)

HGVS:

NC_000019.10:g.11102786C>T
NG_009060.1:g.18406C>T
NM_000527.5:c.313C>TMANE SELECT
NM_001195798.2:c.313C>T
NM_001195799.2:c.191-2434C>T
NM_001195800.2:c.313C>T
NM_001195803.2:c.313C>T
NP_000518.1:p.Pro105Ser
NP_000518.1:p.Pro105Ser
NP_001182727.1:p.Pro105Ser
NP_001182729.1:p.Leu105=
NP_001182732.1:p.Pro105Ser
LRG_274t1:c.313C>T
LRG_274:g.18406C>T
LRG_274p1:p.Pro105Ser
NC_000019.9:g.11213462C>T
NM_000527.4:c.313C>T
c.313C>T

Protein change:

P105S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000442; dbSNP: rs13306510

NCBI 1000 Genomes Browser:

rs13306510

Molecular consequence:

NM_001195799.2:c.191-2434C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.313C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.313C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.313C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.313C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

Recent activity

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zinc finger protein 385B isoform 4 [Homo sapiens]
zinc finger protein 385B isoform 4 [Homo sapiens]
gi|1209601129|ref|NP_001339738.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000294602	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely benign (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 15998910, 9137885 Citation Link,
SCV004820147	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9137885, 15998910, 26345093, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000294602

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely benign
(Mar 25, 2016)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004820147

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 13, 2023)

germline

clinical testing

PubMed (4)
[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	2	not provided	not provided	2	not provided	literature only
not provided	germline	unknown	5	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

A novel point mutation (Pro84-->Ser) of the low density lipoprotein receptor gene in a family with moderate hypercholesterolemia.

Vuorio AF, Turtola H, Kontula K.

Clin Genet. 1997 Mar;51(3):191-5.

PubMed [citation]

PMID:: 9137885

Mutation scanning by meltMADGE: validations using BRCA1 and LDLR, and demonstration of the potential to identify severe, moderate, silent, rare, and paucimorphic mutations in the general population.

Alharbi KK, Aldahmesh MA, Spanakis E, Haddad L, Whittall RA, Chen XH, Rassoulian H, Smith MJ, Sillibourne J, Ball NJ, Graham NJ, Briggs PJ, Simpson IA, Phillips DI, Lawlor DA, Ye S, Humphries SE, Cooper C, Smith GD, Ebrahim S, Eccles DM, Day IN.

Genome Res. 2005 Jul;15(7):967-77.

PubMed [citation]

PMID:: 15998910
PMCID:: PMC1172041

See all PubMed Citations (4)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294602.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (2)
2	not provided	1	not provided	not provided	literature only	PubMed (2)

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

From All of Us Research Program, National Institutes of Health, SCV004820147.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant (also known as p.Pro84Ser in the mature protein) replaces proline with serine at codon 105 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental functional study using RT-PCR of mRNA from a carrier individual has shown that this variant does not affect normal splicing of the primary transcript (PMID: 9137885). This variant has been reported in one individual and multiple relatives affected with moderate hypercholesterolemia (PMID: 9137885), and in another individual affected with moderate hypercholesterolemia (PMID: 15998910). This variant has been reported in multiple individuals affected with familial hypercholesterolemia as well as in two healthy control individuals (PMID: 26345093). This variant has been identified in 23/282822 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		5	not provided	not provided	not provided

Last Updated: May 7, 2024

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