NM_000527.5(LDLR):c.67+1G>T AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 20, 2023
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:: RCV000509520.3

Allele description [Variation Report for NM_000527.5(LDLR):c.67+1G>T]

NM_000527.5(LDLR):c.67+1G>T

Genes:

LDLR-AS1:LDLR antisense RNA 1 [Gene - HGNC]
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.67+1G>T

HGVS:

NC_000019.10:g.11089616G>T
NG_009060.1:g.5236G>T
NM_000527.5:c.67+1G>TMANE SELECT
NM_001195798.2:c.67+1G>T
NM_001195799.2:c.67+1G>T
NM_001195800.2:c.67+1G>T
NM_001195803.2:c.67+1G>T
LRG_274t1:c.67+1G>T
LRG_274:g.5236G>T
NC_000019.9:g.11200292G>T
NM_000527.4:c.67+1G>T
NR_163945.1:n.44C>A

Links:

dbSNP: rs762417023

NCBI 1000 Genomes Browser:

rs762417023

Molecular consequence:

NR_163945.1:n.44C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000527.5:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195798.2:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195799.2:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195800.2:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001195803.2:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

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

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ribonuclease III [Negativibacillus massiliensis]
ribonuclease III [Negativibacillus massiliensis]
gi|1711132997|ref|WP_143529464.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000607409	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004840239	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28964736, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000607409

Fundacion Hipercolesterolemia Familiar - SAFEHEART

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 1, 2016)

germline

research

PubMed (1)
[See all records that cite this PMID]

SCV004840239

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Nov 20, 2023)

germline

clinical testing

PubMed (2)
[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	unknown	1	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.

Defesche JC, Stefanutti C, Langslet G, Hopkins PN, Seiz W, Baccara-Dinet MT, Hamon SC, Banerjee P, Kastelein JJP.

J Clin Lipidol. 2017 Nov - Dec;11(6):1338-1346.e7. doi: 10.1016/j.jacl.2017.08.016. Epub 2017 Sep 4. Erratum in: J Clin Lipidol. 2020 Sep - Oct;14(5):742. doi: 10.1016/j.jacl.2020.09.010.

PubMed [citation]

PMID:: 28964736

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607409.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	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

From All of Us Research Program, National Institutes of Health, SCV004840239.1

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

Description

This variant causes a G to T nucleotide substitution at the canonical +1 position of intron 1 of the LDLR gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in at least one individual affected with familial hypercholesterolemia (PMID: 28964736). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same splice donor site, c.67+1G>A, c.67+1dup, and c.67+2T>A, are reported to be disease-causing (ClinVar variation ID: 431507, 1067553, 250987). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

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

Last Updated: May 7, 2024

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