NM_000527.5(LDLR):c.967G>T (p.Gly323Cys) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Aug 28, 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:: RCV000417282.3

Allele description [Variation Report for NM_000527.5(LDLR):c.967G>T (p.Gly323Cys)]

NM_000527.5(LDLR):c.967G>T (p.Gly323Cys)

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.967G>T (p.Gly323Cys)

Other names:

NM_000527.5(LDLR):c.967G>T

HGVS:

NC_000019.10:g.11110678G>T
NG_009060.1:g.26298G>T
NM_000527.5:c.967G>TMANE SELECT
NM_001195798.2:c.967G>T
NM_001195799.2:c.844G>T
NM_001195800.2:c.463G>T
NM_001195803.2:c.586G>T
NP_000518.1:p.Gly323Cys
NP_000518.1:p.Gly323Cys
NP_001182727.1:p.Gly323Cys
NP_001182728.1:p.Gly282Cys
NP_001182729.1:p.Gly155Cys
NP_001182732.1:p.Gly196Cys
LRG_274t1:c.967G>T
LRG_274:g.26298G>T
LRG_274p1:p.Gly323Cys
NC_000019.9:g.11221354G>T
NM_000527.4:c.967G>T

Protein change:

G155C

Links:

dbSNP: rs373869746

NCBI 1000 Genomes Browser:

rs373869746

Molecular consequence:

NM_000527.5:c.967G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.967G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.844G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.463G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.586G>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000503270	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)	Pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002568018	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely pathogenic (Aug 28, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000503270

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)

Pathogenic
(Dec 16, 2016)

germline

clinical testing

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

SCV002568018

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Likely pathogenic
(Aug 28, 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	3	not provided	not provided	2600	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	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 Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503270.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (1)

Description

subjects mutated among 2600 FH index cases screened = 3 , family member = 1 with co-segregation / other mutation at same codon / Software predictions: Damaging

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		3	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002568018.1

#	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.967G>T (p.Gly323Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP1, PP3, PS4_Supporting 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), so PM2 is met. PP1 - variant segregates with the FH phenotype in 2 informative meiosis (1 from each family) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière): 2 relatives with LDL>75th percentile have the variant, so PP1 is met. PP3 - REVEL = 0.903. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in 4 unrelated index cases who fulfill at least SB Possible criteria for FH from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), so PS4_Supporting is met PP4 - variant meets PM2 and was identified in 4 unrelated index cases who fulfill clinical criteria for FH after alternative causes for high cholesterol were excluded (please see PS4 for details), so PP4 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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