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.226G>C (p.Gly76Arg)

CA042515

1331775 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 4020be23-0433-4d1e-9d5b-828c68b7d8f4

HGVS expressions

NM_000527.5:c.226G>C

NM_000527.5(LDLR):c.226G>C (p.Gly76Arg)

NC_000019.10:g.11102699G>C

CM000681.2:g.11102699G>C

NC_000019.9:g.11213375G>C

CM000681.1:g.11213375G>C

NC_000019.8:g.11074375G>C

NG_009060.1:g.18319G>C

ENST00000558518.6:c.226G>C

ENST00000252444.9:n.480G>C

ENST00000455727.6:c.226G>C

ENST00000535915.5:c.190+2354G>C

ENST00000545707.5:c.226G>C

ENST00000557933.5:c.226G>C

ENST00000557958.1:n.312G>C

ENST00000558013.5:c.226G>C

ENST00000558518.5:c.226G>C

NM_000527.4:c.226G>C

NM_001195798.1:c.226G>C

NM_001195799.1:c.190+2354G>C

NM_001195800.1:c.226G>C

NM_001195803.1:c.226G>C

NM_001195798.2:c.226G>C

NM_001195799.2:c.190+2354G>C

NM_001195800.2:c.226G>C

NM_001195803.2:c.226G>C

Uncertain Significance

PS3_Moderate PP3

PS2 PS4 PS1 PM6 PM2 PM3 PM1 PM4 PM5 BA1 BP2 BP3 BP4 BS4 BS3 BS1 BS2 PP1 PP4

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.226G>C (p.Gly76Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PS3_Moderate and PP3 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: PS3_Moderate: Level 2 assays: PMID 34970301: Heterologous cells (HEK-293), WB and CLSM assays - result: 63% uptake. Result it below 70% of wild-type, so PS3_Moderate is met. PP3: REVEL=0.83. It is above 0.75. So, PP3 is met.

PS3_Moderate

Level 2 assays: PMID 34970301: Heterologous cells (HEK-293), WB and CLSM assays - result: 63% uptake. Result it below 70% of wild-type, so PS3_Moderate is met.

PP3

REVEL=0.83. It is above 0.75. So, PP3 is met.

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

Variant doesn't meet PM2.

PS1

No other missense variant in the codon with the same amino acid change.

PM6

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM2

PopMax MAF= 0.00027 (0.027%) in East Asian exomes+genomes (gnomAD v2.1.1).

PM3

No data available.

PM1

Not on exon 4. Not a cysteine residue.

PM4

No in-frame deletions/insertions

PM5

One other missense variant in the same codon: NM_000527.5(LDLR):c.226G>T (p.Gly76Trp) (ClinVar ID 251081) Uncertain significance by these guidelines There is no variant in the same codon classified as Pathogenic by these guidelines

BA1

FAF= 0.0001062 (0.01062%)

BP2

No data available.

BP3

No in-frame deletions/insertions

BP4

REVEL=0.83. It is above 0.5.

BS4

No data available.

BS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

FAF= 0.0001062 (0.01062%)

BS2

No data available.

PP1

No data available.

PP4

Variant doesn't meet PM2.

Approved on: 2023-04-28

Published on: 2023-04-30

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