NM_000527.5:c.912C>G

Variant names:

• chr19-11107486-C-G
• rs875989909
• NM_000527.5:c.912C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM5 PM2 PP3 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.912C>G (p.Asp304Glu) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PM5, PS4_supporting, PP4 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.PP3 - REVEL = 0.871.It is above 0.75, so PP3 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.910G>C (p.Asp304His) (ClinVar ID 440612) - VUS by these guidelines- NM_000527.5(LDLR):c.911A>T (p.Asp304Val) (ClinVar ID 440613) - VUS by these guidelines- NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID 251517) - Likely pathogenic by these guidelinesThere is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.PS4_supporting - Variant meets PM2 and is identified in at least 2 unrelated index cases: 1 index case who fulfils DLCN>6 criteria for FH from Robarts Research Institute and 1 index case who fulfils Simon Broome criteria for FH from MRC Clinical Sciences Centre, London UK (Tosi et al, 2007)(PMID:17094996), so PS4_Supporting is Met.PP4 - Variant meets PM2 and is identified in at least 2 unrelated index cases as described in PS4, PP4 is Met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10576290/MONDO:0007750/013

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 0.650
• Publications: 8 publications found

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for LDLR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.912C>G	p.Asp304Glu	missense	Exon 6 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.912C>G	p.Asp304Glu	missense	Exon 6 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.789C>G	p.Asp263Glu	missense	Exon 5 of 17	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.912C>G	p.Asp304Glu	missense	Exon 6 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1170C>G	p.Asp390Glu	missense	Exon 6 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.912C>G	p.Asp304Glu	missense	Exon 6 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1457534 Hom.: 0 Cov.: 32 AF XY: 0.00000690 AC XY: 5 AN XY: 725050

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39474

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000811 AC: 9 AN: 1109118

Other (OTH) AF: 0.00 AC: 0 AN: 60076

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Hypercholesterolemia, familial, 1 (7)
3	-	-	Familial hypercholesterolemia (3)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Dyslipidemia (1)
1	-	-	Homozygous familial hypercholesterolemia (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		0.65
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.026	D
Sift4G	Benign	0.071	T
Polyphen		0.81	P
Vest4		0.85
MutPred		0.96		Gain of disorder (P = 0.165)
MVP		1.0
MPC		0.72
ClinPred		0.99	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs875989909; hg19: chr19-11218162;