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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.910G>C (p.Asp304His)

CA404081038

440612 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: c516cee2-601e-4952-a3f1-d8db1acfda92

HGVS expressions

NM_000527.5:c.910G>C

NM_000527.5(LDLR):c.910G>C (p.Asp304His)

NC_000019.10:g.11107484G>C

CM000681.2:g.11107484G>C

NC_000019.9:g.11218160G>C

CM000681.1:g.11218160G>C

NC_000019.8:g.11079160G>C

NG_009060.1:g.23104G>C

ENST00000558518.6:c.910G>C

ENST00000252444.9:n.1164G>C

ENST00000455727.6:c.406G>C

ENST00000535915.5:c.787G>C

ENST00000545707.5:c.529G>C

ENST00000557933.5:c.910G>C

ENST00000558013.5:c.910G>C

ENST00000558518.5:c.910G>C

ENST00000558528.1:n.425G>C

ENST00000560467.1:n.510G>C

NM_000527.4:c.910G>C

NM_001195798.1:c.910G>C

NM_001195799.1:c.787G>C

NM_001195800.1:c.406G>C

NM_001195803.1:c.529G>C

NM_001195798.2:c.910G>C

NM_001195799.2:c.787G>C

NM_001195800.2:c.406G>C

NM_001195803.2:c.529G>C

Uncertain Significance

PP3 PM2 PM5

PS2 PS4 PS3 PS1 PP4 PP1 PM6 PM3 PM1 PM4 PVS1 BA1 BS2 BS4 BS3 BS1 BP7 BP2 BP4

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.910G>C (p.Asp304His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PM5, and PP3 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: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PM5 - 4 other missense variants in the same codon: - NNM_000527.5(LDLR):c.910G>A (p.Asp304Asn) (ClinVar ID 3692) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.911A>T (p.Asp304Val) (ClinVar ID 440613) - VUS by these guidelines - NM_000527.5(LDLR):c.912C>G (p.Asp304Glu) (ClinVar ID 226336) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID 251517) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met. PP3 - REVEL = 0.99. It is above 0.75, so PP3 is Met.

PP3

REVEL = 0.99. It is above 0.75, so PP3 is Met.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.

PM5

4 other missense variants in the same codon: - NNM_000527.5(LDLR):c.910G>A (p.Asp304Asn) (ClinVar ID 3692) - Pathogenic by these guidelines - NM_000527.5(LDLR):c.911A>T (p.Asp304Val) (ClinVar ID 440613) - VUS by these guidelines - NM_000527.5(LDLR):c.912C>G (p.Asp304Glu) (ClinVar ID 226336) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID 251517) - Likely pathogenic by these guidelines There is 1 variant in the same codon classified as Pathogenic by these guidelines, so PM5 is Met.

PS2

No evidence added, so PS2 is Not Met.

PS4

Variant meets PM2, but case-control data not reported, so PS4 is Not Met.

PS3

There is no functional studies reported for this variant, so PS3 is not met.

PS1

There is no other missense variants in the same codon, so PS1 is Not Met.

PP4

Variant meets PM2 but evidence of phenotype data is not reported, so PP4 is Not Met.

PP1

No evidence added of segregation data, so PP1 is Not Met.

PM6

No evidence added, so PM6 is Not Met.

PM3

No case-level data available, so PM3 is Not Met.

PM1

Variant meets PM2 but is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.

PM4

Variant meets PM2 but is missense, so PM4 is Not Met.

PVS1

Variant is missense, so PVS1 is Not Met.

BA1

No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BA1 is Not Met.

BS2

Case-control data not reported, so BS2 is Not Met.

BS4

No evidence added of non-segregation data, so BS4 is Not Met.

BS3

There is no functional studies reported for this variant, so BS3 is not met.

BS1

No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BS1 is Not Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

No case-level data available, so BP2 is Not Met.

BP4

REVEL = 0.99. It is not below 0.50, so BP4 is Not Met.

Approved on: 2021-11-11

Published on: 2022-04-05

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