NM_000527.5(LDLR):c.910G>C (p.Asp304His) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 11, 2021
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:: RCV000508931.6

Allele description [Variation Report for NM_000527.5(LDLR):c.910G>C (p.Asp304His)]

NM_000527.5(LDLR):c.910G>C (p.Asp304His)

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.910G>C (p.Asp304His)

Other names:

NM_000527.5(LDLR):c.910G>C; p.Asp304His

HGVS:

NC_000019.10:g.11107484G>C
NG_009060.1:g.23104G>C
NM_000527.5:c.910G>CMANE SELECT
NM_001195798.2:c.910G>C
NM_001195799.2:c.787G>C
NM_001195800.2:c.406G>C
NM_001195803.2:c.529G>C
NP_000518.1:p.Asp304His
NP_000518.1:p.Asp304His
NP_001182727.1:p.Asp304His
NP_001182728.1:p.Asp263His
NP_001182729.1:p.Asp136His
NP_001182732.1:p.Asp177His
LRG_274t1:c.910G>C
LRG_274:g.23104G>C
LRG_274p1:p.Asp304His
NC_000019.9:g.11218160G>C
NM_000527.4:c.910G>C

Protein change:

D136H

Links:

dbSNP: rs121908030

NCBI 1000 Genomes Browser:

rs121908030

Molecular consequence:

NM_000527.5:c.910G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.910G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.787G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.406G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.529G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000606265	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000607521	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002506360	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Nov 11, 2021)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000606265

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

no assertion criteria provided

Pathogenic

germline

research

SCV000607521

Fundacion Hipercolesterolemia Familiar - SAFEHEART

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 1, 2016)

germline

research

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

SCV002506360

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Uncertain significance
(Nov 11, 2021)

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	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 Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606265.1

#	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 Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607521.1

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506360.1

#	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.910G>C (p.Asp304His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, and PP3 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), so PM2 is Met. PM5 - 4 other missense variants in the same codon: - NNM_000527.5(LDLR):c.910G>A (p.Asp304Asn) (ClinVar ID 3692) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.911A>T (p.Asp304Val) (ClinVar ID 440613) - VUS by these guidelines - NM_000527.5(LDLR):c.912C>G (p.Asp304Glu) (ClinVar ID 226336) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID 251517) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met. PP3 - REVEL = 0.99. It is above 0.75, so PP3 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: May 1, 2024

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