NM_000527.5(LDLR):c.1221C>T (p.His407=) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 29, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000495935.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1221C>T (p.His407=)]

NM_000527.5(LDLR):c.1221C>T (p.His407=)

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.1221C>T (p.His407=)

Other names:

NM_000527.5(LDLR):c.1221C>T; p.His407=

HGVS:

NC_000019.10:g.11113312C>T
NG_009060.1:g.28932C>T
NM_000527.5:c.1221C>TMANE SELECT
NM_001195798.2:c.1221C>T
NM_001195799.2:c.1098C>T
NM_001195800.2:c.717C>T
NM_001195803.2:c.840C>T
NP_000518.1:p.His407=
NP_000518.1:p.His407=
NP_001182727.1:p.His407=
NP_001182728.1:p.His366=
NP_001182729.1:p.His239=
NP_001182732.1:p.His280=
LRG_274t1:c.1221C>T
LRG_274:g.28932C>T
LRG_274p1:p.His407=
NC_000019.9:g.11223988C>T
NM_000527.4:c.1221C>T

Links:

dbSNP: rs778424518

NCBI 1000 Genomes Browser:

rs778424518

Molecular consequence:

NM_000527.5:c.1221C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195798.2:c.1221C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195799.2:c.1098C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195800.2:c.717C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195803.2:c.840C>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000583808	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 23, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000606365	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Benign	germline	research
SCV002817139	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Aug 29, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000583808

U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 23, 2024)

germline

clinical testing

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

SCV000606365

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

no assertion criteria provided

Benign

germline

research

SCV002817139

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Uncertain significance
(Aug 29, 2022)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation

Citations

PubMed

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 U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583808.2

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

Description

Dutch Lipid Clinic Scoring : Probable FH

Description

Additional comments to ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel ClinGen - FDA RECOGNIZED DATABASE (accession SCV002817139.1) of insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4, BP7). New evidence has been collected since original submission in 2017: lack of segregation with hypercholesterolemia in one family (BS4). This variant was observed in trans with distinct pathogenic variants at the LDLR locus, in two independent families (BP2). Therefore this variant is now classified as variant of Uncertain significance.

#	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		1	not provided	1	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606365.1

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

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002817139.1

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

Description

The NM_000527.5(LDLR):c.1221C>T (p.His407=) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, BP4, BP7) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). BP4 - No REVEL, splicing evaluation required. Functional data not available A) not on limits B) does not create AG Variant not predicted to alter splicing BP7 - Variant is synonymous and meets BP4.

#	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: Oct 26, 2024

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