Evidence Repository
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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  • See Evidence submitted by expert panel for details.

Variant: NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr)

CA10585188

251517 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: e9cc60ac-0473-4260-b304-f5a2afe680af
Approved on: 2021-06-08
Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.910G>T
NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr)
ENST00000558518.6:c.910G>T
ENST00000252444.9:n.1164G>T
ENST00000455727.6:c.406G>T
ENST00000535915.5:c.787G>T
ENST00000545707.5:c.529G>T
ENST00000557933.5:c.910G>T
ENST00000558013.5:c.910G>T
ENST00000558518.5:c.910G>T
ENST00000558528.1:n.425G>T
ENST00000560467.1:n.510G>T
NM_000527.4:c.910G>T
NM_001195798.1:c.910G>T
NM_001195799.1:c.787G>T
NM_001195800.1:c.406G>T
NM_001195803.1:c.529G>T
NM_001195798.2:c.910G>T
NM_001195799.2:c.787G>T
NM_001195800.2:c.406G>T
NM_001195803.2:c.529G>T
NC_000019.10:g.11107484G>T
CM000681.2:g.11107484G>T
NC_000019.9:g.11218160G>T
CM000681.1:g.11218160G>T
NC_000019.8:g.11079160G>T
NG_009060.1:g.23104G>T

Likely Pathogenic

Met criteria codes 4
PP4 PP3 PM5_Strong PM2
Not Met criteria codes 22
BP5 BP7 BP2 BP3 BP4 BP1 PVS1 PS2 PS4 PS1 PS3 PP1 PP2 PM3 PM4 PM1 PM6 BA1 BS2 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM5_Strong, PM2, PP3 and PP4) 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: PM5_strong - Four more missense variants described in same codon, of which 2 variants classified as Pathogenic, so PM5_Strong is Met. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.982. PP4 - Variant meets PM2. Identified in 1 FH case who fulfills Simon-Broome criteria for FH in PMID 1301940.
Met criteria codes
PP4
Variant meets PM2. Identified in 1 FH case who fulfills Simon-Broome criteria for FH (plasma cholesterol levels over 600mg/dl and tendon xanthomas) in PMID 1301940. ---- PP4 is Met
PP3
REVEL = 0.982. It is above 0.75, so PP3 is Met
PM5_Strong
Four more missense variants described in same codon: (1)NM_000527.4(LDLR):c.910G>C (p.Asp304His) (ClinVar ID 440612) - classified as Likely pathogenic by these guidelines (2)NM_000527.5(LDLR):c.910G>A (p.Asp304Asn) (ClinVar ID 3692) - classified as Pathogenic by these guidelines (3)NM_000527.4(LDLR):c.911A>T (p.Asp304Val) (ClinVar ID 440613) - classified as Likely pathogenic by these guidelines (4)NM_000527.5(LDLR):c.912C>G (p.Asp304Glu) (ClinVar ID 226336) - classified as Pathogenic by these guidelines --- 2 variants classified as Pathogenic, so PM5_Strong is Met
PM2
No population data was found for this variant in gnomAD (gnomAD v2.1.1)
Not Met criteria codes
BP5
Not applicable
BP7
Missense variant, so BP7 is not applicable
BP2
no individuals with other variants and heterozygous phenotype were identified, so BP2 is Not Met
BP3
Not applicable
BP4
REVEL = 0.982. It is not below 0.15 and PP3 is Met, so BP4 is Not Met
BP1
Not applicable
PVS1
Missense variant, PVS1 Not Met
PS2
no de novo cases were identified, so PS2 is Not Met
PS4
Variant meets PM2. Variant identified in 1 index case fulfilling Simon-Broome criteria for FH from PMID: 1301940, so PS4 is Not Met
PS1
No variant described that leads to the same amino acid change, so PS1 is Not Met
PS3
no functional assays performed, not applicable
PP1
no family members were tested, so PP1 is Not Met
PP2
Not applicable
PM3
Variant meets PM2. Index case from PMID 1301940 has phenotype of Homozygous FH and is compound heterozygous with NM_000527.5(LDLR):c.932A>G (p.Lys311Arg) variant (ClinVar ID 251532) - classified as VUS by these guidelines. --- 2nd variant classified as VUS, so PM3 is Not Met
PM4
Missense variant, not applicable
PM1
Missense at codon 304. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met
PM6
no de novo cases were identified, so PM6 is Not Met
BA1
No population data was found for this variant in gnomAD (gnomAD v2.1.1)
BS2
no unaffected individuals identified with the variant, so BS2 is Not Met
BS4
no family members were tested, so BS4 is Not Met
BS3
no functional assays performed, not applicable
BS1
No population data was found for this variant in gnomAD (gnomAD v2.1.1)
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