19-11113382-G-C

Position:

• chr19-11113382-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3 PP4 PM5 PM3

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.1291G>C (p.Ala431Pro) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, PM5, 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 was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met.PM3 - variant meets PM2 and was identified in:- index case who is homozygous for the variant and has LDL at least 550mg/dl (figure 2A in the paper) from PMID 29502162 (Klaus et al. 2018), Germany.--- individual is homozygous for variant and has an homozygous phenotype, so PM3 is met.PM5 - one other missense variant in the same codon:- NM_000527.5(LDLR):c.1291G>A (p.Ala431Thr)- 2 stars, Pathogenic/Likely pathogenic​ in ClinVar- Pathogenic by these guidelines, so PM5 is met.PP3 - REVEL = 0.939. It is above 0.75, so PP3 is met.PP4 - variant meets PM2 and was identified in 1 index case with DLCN at least 8 (untreated LDL at least 550mg/dl) from PMID 29502162 (Klaus et al., 2018), Germany, so PP4 is met. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023446/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 29)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 8.01

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1291G>C	p.Ala431Pro	missense_variant	9/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1291G>C	p.Ala431Pro	missense_variant	9/18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	Aug 28, 2022	The NM_000527.5(LDLR):c.1291G>C (p.Ala431Pro) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PM3, PM5, 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 was not identified in gnomAD (gnomAD v2.1.1), so PM2 is met. PM3 - variant meets PM2 and was identified in: - index case who is homozygous for the variant and has LDL at least 550mg/dl (figure 2A in the paper) from PMID 29502162 (Klaus et al. 2018), Germany. --- individual is homozygous for variant and has an homozygous phenotype, so PM3 is met. PM5 - one other missense variant in the same codon: - NM_000527.5(LDLR):c.1291G>A (p.Ala431Thr) - 2 stars, Pathogenic/Likely pathogenic in ClinVar - Pathogenic by these guidelines, so PM5 is met. PP3 - REVEL = 0.939. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 1 index case with DLCN at least 8 (untreated LDL at least 550mg/dl) from PMID 29502162 (Klaus et al., 2018), Germany, so PP4 is met. -
Likely pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Familial hypercholesterolemia Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The p.Ala431Pro variant in LDLR has been reported in 1 German individual with familial hypercholesterolemia (PMID: 29502162), and was absent from large population studies. This variant has also been reported in ClinVar as likely pathogenic (Variation ID: 36454). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Ala431Thr, have been reported in association with disease in the literature and Clinvar, supporting that a change at this position may not be tolerated (PMID: 20506408, 21382890, 17347910, 12837857, 22698793, 20538126, 20145306, 2088165, 10447263, 17765246, 15200491, 11810272,17765246/Variation ID: 3695). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM5, PP3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;.;.;.;.;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.93
MutPred		0.84		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);.;.;.;Gain of relative solvent accessibility (P = 0.09);
MVP		1.0
MPC		0.93
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.95
gMVP		1.0

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: rs28942079; hg19: chr19-11224058;