NM_000527.5(LDLR):c.1067A>C (p.Asp356Ala) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Apr 28, 2023
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:: RCV000238074.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1067A>C (p.Asp356Ala)]

NM_000527.5(LDLR):c.1067A>C (p.Asp356Ala)

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.1067A>C (p.Asp356Ala)

Other names:

NM_000527.5(LDLR):c.1067A>C

HGVS:

NC_000019.10:g.11111520A>C
NG_009060.1:g.27140A>C
NM_000527.5:c.1067A>CMANE SELECT
NM_001195798.2:c.1067A>C
NM_001195799.2:c.944A>C
NM_001195800.2:c.563A>C
NM_001195803.2:c.686A>C
NP_000518.1:p.Asp356Ala
NP_000518.1:p.Asp356Ala
NP_001182727.1:p.Asp356Ala
NP_001182728.1:p.Asp315Ala
NP_001182729.1:p.Asp188Ala
NP_001182732.1:p.Asp229Ala
LRG_274t1:c.1067A>C
LRG_274:g.27140A>C
LRG_274p1:p.Asp356Ala
NC_000019.9:g.11222196A>C
NM_000527.4:c.1067A>C
c.1067A>C

Protein change:

D188A

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001347; dbSNP: rs879254777

NCBI 1000 Genomes Browser:

rs879254777

Molecular consequence:

NM_000527.5:c.1067A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1067A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.944A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.563A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.686A>C - missense variant - [Sequence Ontology: SO:0001583]

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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protein IL-40 precursor [Homo sapiens]
protein IL-40 precursor [Homo sapiens]
gi|251823704|ref|NP_001156547.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295198	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000503293	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004022454	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely pathogenic (Apr 28, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295198

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely pathogenic
(Mar 25, 2016)

germline

literature only

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

Citation Link,

SCV000503293

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 16, 2016)

germline

clinical testing

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

SCV004022454

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Likely pathogenic
(Apr 28, 2023)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	yes	2	not provided	not provided	2601	not provided	clinical testing, literature only

Citations

PubMed

Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

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 LDLR-LOVD, British Heart Foundation, SCV000295198.2

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

#	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

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503293.1

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

Description

subject mutated among 2600 FH index cases screened = 1 , family members = 2 /previously described in association with FH / Software predictions: Conflicting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		1	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV004022454.1

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

Description

The variant NM_000527.5(LDLR):c.1067A>C (p.Asp356Ala) is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, PP1, PP3, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP1 - variant segregates with FH phenotype in 2 informative meiosis in 1 family from Centre de Genetique Moleculaire et Chromosomique, Unite de genetique de l'Obeste et des Dyslipidemies (APHP Sorbonne Univeristie Hopitalde la Pitie-Salpetriere): 2 affected family members have the variant. PP3 - REVEL=0.947 PP4 - Variant meets PM2 and is identified in at least 1 index case meeting clinical diagnostic criteria for FH, after alternative causes of high cholesterol were excluded. PM5: 4 other missense variants in the same codon: 1) NM_000527.5(LDLR):c.1066G>T (p.Asp356Tyr) (ClinVar ID 226345) - Pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1066G>C (p.Asp356His) (ClinVar ID 251644) - Likely Pathogenic by these guidelines. 3) NM_000527.5(LDLR):c.1066G>A (p.Asp356Asn) (ClinVar ID 251643) - Unknown Significance by these guidelines. 4) NM_000527.5(LDLR):c.1067A>T (p.Asp356Val) (ClinVar ID 440623) - Likely Pathogenic by these guidelines. There is 1 variant (p.Asp356Tyr) in the same codon classified as Pathogenic by these guidelines. So PM5 is met.

#	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: Jun 23, 2024

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