rs879254777

Positions:

• chr19-11111520-A-C
• chr19-11111520-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1067A>C	p.Asp356Ala	missense_variant	8/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1067A>C	p.Asp356Ala	missense_variant	8/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1 , family members = 2 /previously described in association with FH / Software predictions: Conflicting -
Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Apr 28, 2023	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. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -

Computational scores

Source: dbNSFP v4.3

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;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.8	D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.80
MutPred		0.92		Loss of disorder (P = 0.0513);Loss of disorder (P = 0.0513);.;.;.;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs879254777; hg19: chr19-11222196;