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.1055G>A (p.Cys352Tyr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA023408

36450 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 1b7719a1-ebea-4124-9925-8b5037b8efc0

Approved on: 2021-06-08

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.1055G>A

NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr)

ENST00000558518.6:c.1055G>A

ENST00000252444.9:n.1309G>A

ENST00000455727.6:c.551G>A

ENST00000535915.5:c.932G>A

ENST00000545707.5:c.674G>A

ENST00000557933.5:c.1055G>A

ENST00000558013.5:c.1055G>A

ENST00000558518.5:c.1055G>A

ENST00000560173.1:n.54G>A

ENST00000560467.1:n.541-748G>A

NM_000527.4:c.1055G>A

NM_001195798.1:c.1055G>A

NM_001195799.1:c.932G>A

NM_001195800.1:c.551G>A

NM_001195803.1:c.674G>A

NM_001195798.2:c.1055G>A

NM_001195799.2:c.932G>A

NM_001195800.2:c.551G>A

NM_001195803.2:c.674G>A

NC_000019.10:g.11110766G>A

CM000681.2:g.11110766G>A

NC_000019.9:g.11221442G>A

CM000681.1:g.11221442G>A

NC_000019.8:g.11082442G>A

NG_009060.1:g.26386G>A

Likely Pathogenic

PP4 PP3 PM2 PM1 PS4_Supporting

PS2 PS3 PS1 PP1 PP2 PM6 PM3 PM4 PM5 PVS1 BA1 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.1055G>A (p.Cys352Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, 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: PM1 - Variant meets PM2 and alters Cys340, one of the cysteine residues listed. PM2 - PopMax MAF = 0.00005782 (0.006%) in Latino/Admixed American exomes (gnomAD v2.1.1). PP3 - REVEL: 0,98. PP4 - Variant meets PM2. Identified in 1 FH case from Center of molecular biology and gene therapy who fulfills Simon-Broome criteria and in 1 FH case published in PMID: 30592178 who fulfills DLCN criteria. PS4_supporting - Variant meets PM2. Variant identified in 2 index cases with clinical FH criteria.

PP4

Variant meets PM2. Identified in 1 FH case from Center of molecular biology and gene therapy who fulfills Simon-Broome criteria and in 1 FH case published in PMID: 30592178 who fulfills DLCN criteria.

PP3

REVEL: 0,98. Score is above 0,75.

PM2

PopMax MAF = 0.00005782 (0.006%) in Latino/Admixed American exomes (gnomAD v2.1.1). MAF is under 0.02%

PM1

Variant meets PM2 and alters Cys340, one of the cysteine residues listed, so PM1 is met

PS4_Supporting

Variant meets PM2. Variant identified in 2 index cases (1 case from Center of molecular biology and gene therapy with Simon-Broome criteria; 1 case in PMID: 30592178 with DLCN criteria).

PS2

No de novo cases were identified.

PS3

No functional assays performed/found - not applicable.

PS1

Variant meets PM1, so PS1 is not applicable

PP1

Variant segregates with phenotype in 1 informative meiosis in 1 family from GeneDx Inc. laboratory. Minimal number of meioses is 2.

PP2

Not applicable.

PM6

No de novo cases were identified.

PM3

Not identified in individuals with other variants.

PM4

Missense variant.

PM5

Variant meets PM1, so PM5 is not applicable

PVS1

Missense variant.

BA1

FAF = 0.000009580 (0.0009580%) in Latino/Admixed American exomes (gnomAD v2.1.1). FAF is not above 0.5%

BS2

No unaffected individuals identified with the variant.

BS4

No variant negative family members were tested.

BS3

No functional assays performed/found - not applicable.

BS1

FAF = 0.000009580 (0.0009580%) in Latino/Admixed American exomes (gnomAD v2.1.1). FAF is not above 0.2%

BP2

Not identified in individuals with other variants.

BP3

not applicable

BP4

REVEL: 0,98. Score is not below 0,15. PP3 met.

BP1

Not applicable.

BP5

Not applicable.

BP7

Missense variant.

Curation History

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