rs372828849

Variant names:

• chr19-11102743-T-A
• rs372828849
• NM_000527.5:c.270T>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11102743-T-A
• chr19-11102743-T-C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP1_Strong PM5 PM2 PP3 PP4 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence PP1_Strong, PM2, PM5, PP3, PP4 and PS4_Supporting 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: PP1_strong - variant segregates with FH phenotype in 11 informative meiosis from 2 families from PMID 20809525 (Marduel et al., 2010): F1: 4 affected relatives have the variant and 3 unaffected relatives do not have the variant; F2: 3 affected relatives have the variant and 1 unaffected relative does not have the variant, so PP1_Strong is met.PM2 - This variant was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PM5 - 4 other missense variants is the same codon:- NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) - Likely pathogenic by these guidelines- NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines- NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) - Likely pathogenic by these guidelines- NM_000527.5(LDLR):c.269A>G (p.Asp90Gly) - Pathogenic by these guidelinesThere is 1 variant classified as Pathogenic by these guidelines, so PM5 is met.PP3 - REVEL = 0.833. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in 4 index cases with SB criteria of FH (total and LDL-cholesterol levels above the 95th percentile of a sex and age-matched French population and autosomal dominant transmission of hypercholesterolemia in the family) from PMID 20809525 (Marduel et al., 2010), so PP4 is met.PS4_supporting - variant meets PM2 and was identified in 4 index cases with SB criteria of FH from PMID 20809525 (Marduel et al., 2010), (see PP4 for details), so PS4_Supporting is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10584821/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: -0.799
• Publications: 6 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: Pathogenic. The variant received 11 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.
• 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.270T>A	p.Asp90Glu	missense	Exon 3 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.270T>A	p.Asp90Glu	missense	Exon 3 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195800.2		c.270T>A	p.Asp90Glu	missense	Exon 3 of 16	NP_001182729.1	P01130-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.270T>A	p.Asp90Glu	missense	Exon 3 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.528T>A	p.Asp176Glu	missense	Exon 3 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.270T>A	p.Asp90Glu	missense	Exon 3 of 18	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Hypercholesterolemia, familial, 1 (5)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	6.4
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		-0.80
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.75
MutPred		0.91		Loss of loop (P = 0.1258)
MVP		1.0
MPC		0.78
ClinPred		1.0	D
GERP RS		-2.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.99
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: rs372828849; hg19: chr19-11213419;