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]

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Variant: NM_000527.5(LDLR):c.58G>A (p.Gly20Arg)

CA023728

161272 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: be4b2a4c-4d4f-4372-99c1-a538940653d5

Approved on: 2021-06-07

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.58G>A

NM_000527.5(LDLR):c.58G>A (p.Gly20Arg)

NC_000019.10:g.11089606G>A

CM000681.2:g.11089606G>A

NC_000019.9:g.11200282G>A

CM000681.1:g.11200282G>A

NC_000019.8:g.11061282G>A

NG_009060.1:g.5226G>A

ENST00000558518.6:c.58G>A

ENST00000455727.6:c.58G>A

ENST00000535915.5:c.58G>A

ENST00000545707.5:c.58G>A

ENST00000557933.5:c.58G>A

ENST00000557958.1:n.144G>A

ENST00000558013.5:c.58G>A

ENST00000558518.5:c.58G>A

ENST00000560502.5:n.144G>A

NM_000527.4:c.58G>A

NM_001195798.1:c.58G>A

NM_001195799.1:c.58G>A

NM_001195800.1:c.58G>A

NM_001195803.1:c.58G>A

NM_001195798.2:c.58G>A

NM_001195799.2:c.58G>A

NM_001195800.2:c.58G>A

NM_001195803.2:c.58G>A

NR_163945.1:n.54C>T

Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

PP1_Moderate BS2 BS4 BS3

PS2 PS4 PS1 PS3 BA1 PP4 PP3 PP2 PM6 PM2 PM3 PM4 PM1 PM5 PVS1 BS1 BP4 BP1 BP2 BP3 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

The NM_000527.5(LDLR):c.58G>A (p.Gly20Arg) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes (BS2, BS3, BS4 and PP1_Moderate) 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: BS2 - Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database. BS3 - Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met. BS4 - Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). PP1_moderate - variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy. Variant has 3 strong evidence codes towards Benign, enough to classify as Benign, and only 1 moderate evidence code towards Pathogenic. The Benign criteria overwhelms the Pathogenic criteria, so we are confident in classifying this variant as Benign.

PP1_Moderate

variant segregates with FH phenotype in 5 informative meiosis from Centre of molecular biology and gene therapy. ---- PP1_Moderate is Met

BS2

Variant identified in 5 unaffected relatives from Centre of molecular biology and gene therapy and 1 elderly heterozygous from the ABraOM database. --- BS2 is Met

BS4

Variant does not segregate with FH phenotype in 8 informative meiosis from at least 3 families from different labs (Centre of molecular biology and gene therapy, University of British Columbia and Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge): 8 affected family members do not have the variant. ---- BS4 is Met

BS3

Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- although not quantified, assume whole cycle is above 90% of wild-type, so BS3 is Met

PS2

no de novo cases were identified, so PS2 is Not Met

PS4

variant does not meet PM2, so PS4 is Not Met

PS1

No variant described that leads to the same amino acid change, so PS1 is Not Met

PS3

Level 1 assays: PMID 27175606: Heterologous cells (CHO), CLSM assays - result - normal cell surface LDLR, normal LDL-LDLR binding. ---- results are not below 70% of wild-type, so PS3 is Not Met

BA1

FAF = 0.0009803 (0.098%) in exomes of european non-finnish (gnomAD v2.1.1). FAF is not above 0.5%, so BA1 is Not Met.

PP4

Variant does not meet PM2, so PP4 is Not Met

PP3

REVEL = 0.558. It is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) variant not on limits. B) variant is exonic and at least 50bp downstream from canonical acceptor site, but it does not create GT. C) there is no GT nearby. No splicing prediction is applicable, so PP3 is Not Met

PP2

Not applicable

PM6

no de novo cases were identified, so PM6 is Not Met

PM2

PopMax MAF = 0.002460 (0.246%) in Ashkenazi Jewish exomes (gnomAD v2.1.1).

PM3

Variant meets PM2 and is identified in compound heterozygocity with other variants in 3 index cases from Centre of molecular biology and gene therapy. --- 2nd variant and phenotypes are not specified, so PM3 is Not Met

PM4

Missense variant, not applicable

PM1

Missense at codon 20. PM2 is Not Met, it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met

PM5

One more missense variant described in same codon: (1)NM_000527.4(LDLR):c.59G>A (p.Gly20Glu) (ClinVar ID 631358) - VUS by these guidelines --- variant is classified as VUS, so PM5 is Not Met

PVS1

Missense variant, PVS1 Not Met

BS1

FAF = 0.0009803 (0.098%) in exomes of european non-finnish (gnomAD v2.1.1). FAF is not above 0.2%, so BS1 is Not Met.

BP4

REVEL = 0.558. It is not below 0.15, so BS4 is Not Met

BP1

Not applicable

BP2

variant identified in (1) 1 index case with heterozygous FH phenotype and another LDLR variant 'LDLR PATH HET (phase unknown)', from GeneDx Inc. (#4). --- 2nd variant is not specified, so BP2 is Not Met. (2) 1 index case with heterozygous FH phenotype with also NM_000527.5(LDLR):c.974G>A p.Cys325Tyr (ClinVar ID 251580), classified as Likely pathogenic by these guidelines, from University of British Columbia. --- 2nd variant is not classified as Pathogenic, so BS2 is not met --- BP2 is Not Met

BP3

Not applicable

BP5

Not applicable

BP7

Missense variant, so BP7 is not applicable

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