Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000527.5(LDLR):c.1057G>A (p.Glu353Lys)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA023410

161275 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: fee5765d-cb59-4e59-a7cd-004cbd0f55f9

Approved on: 2025-01-31

Published on: 2025-03-24

HGVS expressions

NM_000527.5:c.1057G>A

NM_000527.5(LDLR):c.1057G>A (p.Glu353Lys)

NC_000019.10:g.11110768G>A

CM000681.2:g.11110768G>A

NC_000019.9:g.11221444G>A

CM000681.1:g.11221444G>A

NC_000019.8:g.11082444G>A

NG_009060.1:g.26388G>A

ENST00000252444.10:c.1315G>A

ENST00000559340.2:c.1057G>A

ENST00000560467.2:c.941-746G>A

ENST00000558518.6:c.1057G>A

ENST00000252444.9:c.1311G>A

ENST00000455727.6:c.553G>A

ENST00000535915.5:c.934G>A

ENST00000545707.5:c.676G>A

ENST00000557933.5:c.1057G>A

ENST00000558013.5:c.1057G>A

ENST00000558518.5:c.1057G>A

ENST00000560173.1:n.56G>A

ENST00000560467.1:c.541-746G>A

NM_000527.4:c.1057G>A

NM_001195798.1:c.1057G>A

NM_001195799.1:c.934G>A

NM_001195800.1:c.553G>A

NM_001195803.1:c.676G>A

NM_001195798.2:c.1057G>A

NM_001195799.2:c.934G>A

NM_001195800.2:c.553G>A

NM_001195803.2:c.676G>A

Uncertain Significance

PS4_Supporting PM2 PP4

PM1 PM5 BP4 PS3 PP3

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1057G>A (p.Glu353Lys) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2: PopMax MAF= 0.00002 (0.002%) in European (Non-Finnish) in genomes+exomes (gnomAD v4.1.0). PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 4 cases (1 with possible FH by Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, France; 1 with DLCN score >=6 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 1 case in PMID 33994402 (Huang et al., 2022), Taiwan, and 1 case in PMID 34998859 (Pillai et al., 2022), India, with country-specific FH criteria), after alternative causes of high cholesterol were excluded.

PS4_Supporting

PS4 - Variant meets PM2 and is identified in 4 patients (1 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) with Simon Broome possible, 1 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France) DLCN score >=6 , 1 in PMID: 33994402 and 1 in PMID: 34998859 with country-specific FH criteria. There are also 69 patients (1 from Laboratory of Genetics and Molecular Cardiology with LDL>210mg/dl), 54 from PMID: 20506408, 1 from PMID: 15823288, 10 from PMID: 23833242 and 2 from PMID: 36752612 but clinical criteria are not clear. In addition, the variant is reported in PMID: 30971288 and PMID: 28502495 but the number of patients is not specified (very high prevalence of the variant in FH phenotypes).

PM2

PM2 - PopMax MAF= 0.00002 (0.002%) in European (Non-Finnish) in genomes+exomes (gnomAD v4.1.0). So PM2 is Met

PP4

PP4 - Variant meets PM2 and is identified in 4 patients (1 from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) with Simon Broome possible, 1 from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France) DLCN score >=6 , 1 in PMID: 33994402 and 1 in PMID: 34998859 with country-specific FH criteria after alternative causes of high cholesterol were excluded. There are also 69 patients (1 from Laboratory of Genetics and Molecular Cardiology with LDL>210mg/dl), 54 from PMID: 20506408, 1 from PMID: 15823288, 10 from PMID: 23833242 and 2 from PMID: 36752612 but clinical criteria are not clearl. In addition, the variant is reported in PMID: 30971288 and PMID: 28502495 but the number of patients is not specified (very high prevalence of the variant in FH phenotypes).

PM1

PM1 - Variant meets PM2 but it is not located in exon 4 (located in exon 7) and is not affecting one the highly conserved cysteins.

PM5

PM5 - 1 variant (c.1057G>C, p.Glu353Gln) in the same codon but it is not classified as pathogenic by these guidelines.

BP4

BP4 - REVEL = 0.62. It is below 0.75. Splicing evaluation needed. Functional data on splicing not available. A) not on limits B) does not create GT C) GT nearby Variant score/wt score >=1. >variant cryptic score TGCAAAGATA MAXENT: -27.40 >wt cryptic score TGCGAAGATA MAXENT: -19.22 >canonical score AAGGTGATT MAXENT: 5.88 Variant score (1.42) is not predicted to alter splicing. So, BP4 is not met.

PS3

PS3 - In vitro microscopy assays in HeLa cells: LDLR activity - unclear.

PP3

PP3 - REVEL = 0.62. It is below 0.75. Splicing evaluation needed. Functional data on splicing not available. A) not on limits B) does not create GT C) GT nearby. Variant score/wt score >=1. >variant cryptic score TGCAAAGATA/MAXENT: -27.40 >wt cryptic score TGCGAAGATA/MAXENT: -19.22 >canonical score AAGGTGATT/MAXENT: 5.88 Although the variant score (variant cryptic score/wt cryptic score) is 1.42, which is above 0.9 and therefore predicted to alter splicing, the variant score is more negative than the wt score. As a result, PP3 will not be applied despite the ratio.

Curation History

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