NM_000527.5(LDLR):c.1060+10G>A AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 9, 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:: RCV001242346.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1060+10G>A]

NM_000527.5(LDLR):c.1060+10G>A

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.1060+10G>A

HGVS:

NC_000019.10:g.11110781G>A
NG_009060.1:g.26401G>A
NM_000527.5:c.1060+10G>AMANE SELECT
NM_001195798.2:c.1060+10G>A
NM_001195799.2:c.937+10G>A
NM_001195800.2:c.556+10G>A
NM_001195803.2:c.679+10G>A
LRG_274t1:c.1060+10G>A
LRG_274:g.26401G>A
NC_000019.9:g.11221457G>A
NM_000527.4(LDLR):c.1060+10G>A
NM_000527.4:c.1060+10G>A
c.1060+10G>A
p.(Asp354Glyfs*20)

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000880;

Molecular consequence:

NM_000527.5:c.1060+10G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.1060+10G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.937+10G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.556+10G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.679+10G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295175	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Uncertain significance (Mar 25, 2016)	germline	literature only	PubMed (8) [See all records that cite these PMIDs] 16542394, 26332594, 28965616, 34456049, 36991406, 12436241, 15823288, 23375686 Citation Link,
SCV001415427	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 9, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12436241, 15823288, 23375686, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295175

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Uncertain significance
(Mar 25, 2016)

germline

literature only

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV001415427

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 9, 2022)

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	3	not provided	not provided	3	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia.

Brusgaard K, Jordan P, Hansen H, Hansen AB, Hørder M.

Clin Genet. 2006 Mar;69(3):277-83.

PubMed [citation]

PMID:: 16542394

Identification of Medically Actionable Secondary Findings in the 1000 Genomes.

Olfson E, Cottrell CE, Davidson NO, Gurnett CA, Heusel JW, Stitziel NO, Chen LS, Hartz S, Nagarajan R, Saccone NL, Bierut LJ.

PLoS One. 2015;10(9):e0135193. doi: 10.1371/journal.pone.0135193.

PubMed [citation]

PMID:: 26332594
PMCID:: PMC4558085

See all PubMed Citations (9)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295175.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (8)
2	not provided	1	not provided	not provided	literature only	PubMed (8)
3	not provided	1	not provided	not provided	literature only	PubMed (8)

Description

At least 7 reports of c.1060+10G>A in confirmed unrelated FH cases have been made (PMID: 12436241; 16542394; 23375686; 28965616; 36991406) allowing PS4_moderate to be scored. A further 3 three reports have also been published, but without a confirmed diagnosis (PMID: 15823288; 26332594; 34456049). PM2 and PP4 can also be scored, allowing a Uncertain significance classification to be made.

#	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
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001415427.2

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

Description

This sequence change falls in intron 7 of the LDLR gene. It does not directly change the encoded amino acid sequence of the LDLR protein. This variant is present in population databases (rs12710260, gnomAD 0.006%). This variant has been observed in individual(s) with hypercholesterolemia (PMID: 12436241, 15823288, 23375686). ClinVar contains an entry for this variant (Variation ID: 251625). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

#	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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