chr19-11110688-C-T

Variant names:

• chr19-11110688-C-T
• rs879254747
• NM_000527.5:c.977C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000527.5(LDLR):c.977C>T (p.Ser326Phe) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, 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 is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.PM5 - There are 2 other missense variants in the same codon:(1) NM_000527.5(LDLR):c.977C>G (p.Ser326Cys) - 2 stars, Likely pathogenic in ClinVar; Pathogenic by these guidelines (FH VCEP training August 2020).(2) NM_000527.5(LDLR):c.976T>C (p.Ser326Pro) - 1 star, VUS in ClinVar; VUS by these guidelines (PM2, PM5, PP3) with no case data.There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is metPP3 - REVEL = 0.937. It is above 0.75, so PP3 is met.PP4- variant meets PM2 and was identified in 1 index case who fulfills SB criteria (clinical criteria according to PMID 8891383 (Chaves et al., 1996): TC and LDL-C over the 95th percentile corrected for age and sex, with TG not exceeding 200 mg/dl; plus two of the following: tendon xanthomata, premature coronary heart disease in the proband or in a first-degree relative, and hypercholesterolemic children in the family) from PMID 11668640 (García-García et al. 2001), Spain; so PP4 is met LINK:https://erepo.genome.network/evrepo/ui/classification/CA10585236/MONDO:0007750/013

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLR NM_000527.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 5.87

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 6 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.
• 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 rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.977C>T	p.Ser326Phe	missense_variant	Exon 7 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.977C>T	p.Ser326Phe	missense_variant	Exon 7 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:2

Jan 28, 2022

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000527.5(LDLR):c.977C>T (p.Ser326Phe) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, 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 is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PM5 - There are 2 other missense variants in the same codon: (1) NM_000527.5(LDLR):c.977C>G (p.Ser326Cys) - 2 stars, Likely pathogenic in ClinVar; Pathogenic by these guidelines (FH VCEP training August 2020). (2) NM_000527.5(LDLR):c.976T>C (p.Ser326Pro) - 1 star, VUS in ClinVar; VUS by these guidelines (PM2, PM5, PP3) with no case data. There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is met PP3 - REVEL = 0.937. It is above 0.75, so PP3 is met. PP4 - variant meets PM2 and was identified in 1 index case who fulfills SB criteria (clinical criteria according to PMID 8891383 (Chaves et al., 1996): TC and LDL-C over the 95th percentile corrected for age and sex, with TG not exceeding 200 mg/dl; plus two of the following: tendon xanthomata, premature coronary heart disease in the proband or in a first-degree relative, and hypercholesterolemic children in the family) from PMID 11668640 (García-García et al. 2001), Spain; so PP4 is met -

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.;H
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.89
MutPred		0.93		Loss of disorder (P = 0.042);Loss of disorder (P = 0.042);.;.;.;Loss of disorder (P = 0.042);
MVP		1.0
MPC		0.84
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.96

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: rs879254747; hg19: chr19-11221364;