19-11111520-A-C

Variant names:

• chr19-11111520-A-C
• rs879254777
• NM_000527.5:c.1067A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM5 PM2 PP3 PP1 PP4

This summary comes from the ClinGen Evidence Repository: 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=0.947PP4 - 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585287/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.21
• Publications: 5 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

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

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.1067A>C	p.Asp356Ala	missense	Exon 8 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1067A>C	p.Asp356Ala	missense	Exon 8 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.944A>C	p.Asp315Ala	missense	Exon 7 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.1067A>C	p.Asp356Ala	missense	Exon 8 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1325A>C	p.Asp442Ala	missense	Exon 8 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1067A>C	p.Asp356Ala	missense	Exon 8 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Hypercholesterolemia, familial, 1 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		9.2
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.80
MutPred		0.92		Loss of disorder (P = 0.0513)
MVP		1.0
MPC		0.89
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.99
Mutation Taster		=0/100	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: rs879254777; hg19: chr19-11222196;