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.910G>A (p.Asp304Asn)

CA023792

3692 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 586da900-0f67-479c-89aa-50f096de6db6

HGVS expressions

NM_000527.5:c.910G>A

NM_000527.5(LDLR):c.910G>A (p.Asp304Asn)

NC_000019.10:g.11107484G>A

CM000681.2:g.11107484G>A

NC_000019.9:g.11218160G>A

CM000681.1:g.11218160G>A

NC_000019.8:g.11079160G>A

NG_009060.1:g.23104G>A

ENST00000558518.6:c.910G>A

ENST00000252444.9:n.1164G>A

ENST00000455727.6:c.406G>A

ENST00000535915.5:c.787G>A

ENST00000545707.5:c.529G>A

ENST00000557933.5:c.910G>A

ENST00000558013.5:c.910G>A

ENST00000558518.5:c.910G>A

ENST00000558528.1:n.425G>A

ENST00000560467.1:n.510G>A

NM_000527.4:c.910G>A

NM_001195798.1:c.910G>A

NM_001195799.1:c.787G>A

NM_001195800.1:c.406G>A

NM_001195803.1:c.529G>A

NM_001195798.2:c.910G>A

NM_001195799.2:c.787G>A

NM_001195800.2:c.406G>A

NM_001195803.2:c.529G>A

Pathogenic

PS3_Moderate PS4 PP4 PP3 PP1_Strong PM2 PM3

PVS1 BS2 BS4 BS3 BS1 BP7 BP2 BP4 PS2 PS1 BA1 PM6 PM1 PM4 PM5

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>A (p.Asp304Asn) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS3_moderate, PS4, PP1_strong, PM3 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: PM2 - PopMax MAF = 0.0001203 (0.01203%) in African/African American genomes (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.883. It is above 0.75, so PP3 is Met. PS3_moderate - 2 Level 2 assays performed by different labs: PMID 2088165: Homozygous patient cells, 125I-LDL assays - result - 5-15% LDLR activity. PMID 6438436: Homozygous patient cells, 125I-LDL assays - result - 5-10% LDLR activity. 2 Level 3 assays performed by different labs: PMID 4061492: Heterozygous patient cells, 125I-LDL assays - result - 20-30% LDLR activity PMID 6438436: Heterozygous patient cells, 125I-LDL assays - result - 25-50% LDLR activity ---- all functional studies are consistent with damaging effect, so PS3_Moderate is Met. PS4 - Variant meets PM2 and is identified in at least 14 unrelated index cases: 4 index cases who fulfill Simon-Broome criteria for FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 7 unrelated index cases who fulfill Simon-Broome criteria for FH from Malaysia (Al-Khateeb et al, 2011) (PMID: 21418584); 1 index case who fulfills modified Simon-Broome criteria for FH (pretreatment LDL-C >95th percentile for age and sex, with (1) tendon xanthoma (proband or first-degree relative) or (2) either first-degree relative with premature CHD (<55 years of age in men or 65 years of age in women) or pretreatment LDL-C >95th percentile for age and sex) from Dallas, TX, USA (Ahmad et al, 2011) (PMID: 23064986); 1 index case who fulfils Simon-Broome criteria from MRC Clinical Sciences Centre, London UK (Tosi et al, 2007)(PMID: 17094996); and 1 index case with clinical diagnosis of FH (based on (1) a plasma LDL cholesterol concentration above the 95th percentile for age and sex and (2) the presence of xanthoma or coronary heart disease in the proband or at least one first degree relative with type IIa hypercholesterolemia, xanthoma, or CVD) from France (Amsellem et al, 2002) (PMID: 12436241), so PS4 is Met. PP1_strong - Variant segregates with FH phenotype in at least 6 informative meiosis from 3 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): 6 affected family members have the variant, so PP1_Strong is Met. PM3 - Variant meets PM2 and is identified in an index case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with homozygous FH phenotype (14.9 mmol/L) and LDLR c.761A>C/p.(Gln254Pro), classified as Likely pathogenic by these guidelines, in trans, so PM3 is Met. PP4 - Variant meets PM2 and is identified in at least 14 unrelated index cases as described in PS4, PP4 is Met.

PS3_Moderate

2 Level 2 assays performed by different labs: PMID 2088165: Homozygous patient cells, 125I-LDL assays - result - 5-15% LDLR activity. PMID 6438436: Homozygous patient cells, 125I-LDL assays - result - 5-10% LDLR activity. 2 Level 3 assays performed by different labs: PMID 4061492: Heterozygous patient cells, 125I-LDL assays - result - 20-30% LDLR activity PMID 6438436: Heterozygous patient cells, 125I-LDL assays - result - 25-50% LDLR activity ---- all functional studies are consistent with damaging effect, so PS3_Moderate is Met.

PS4

Variant meets PM2 and is identified in at least 14 unrelated index cases: 4 index cases who fulfill Simon-Broome criteria for FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 7 unrelated index cases who fulfill Simon-Broome criteria for FH from Malaysia (Al-Khateeb et al, 2011) (PMID: 21418584); 1 index case who fulfills modified Simon-Broome criteria for FH (pretreatment LDL-C >95th percentile for age and sex, with (1) tendon xanthoma (proband or first-degree relative) or (2) either first-degree relative with premature CHD (<55 years of age in men or 65 years of age in women) or pretreatment LDL-C >95th percentile for age and sex) from Dallas, TX, USA (Ahmad et al, 2011) (PMID: 23064986); 1 index case who fulfils Simon-Broome criteria from MRC Clinical Sciences Centre, London UK (Tosi et al, 2007)(PMID: 17094996); and 1 index case with clinical diagnosis of FH (based on (1) a plasma LDL cholesterol concentration above the 95th percentile for age and sex and (2) the presence of xanthoma or coronary heart disease in the proband or at least one first degree relative with type IIa hypercholesterolemia, xanthoma, or CVD) from France (Amsellem et al, 2002) (PMID: 12436241), so PS4 is Met.

PP4

Variant meets PM2 and is identified in at least 14 unrelated index cases: 4 index cases who fulfill Simon-Broome criteria for FH from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation); 7 unrelated index case who fulfill Simon-Broome criteria for FH from Malaysia (Al-Khateeb et al, 2011) (PMID: 21418584); 1 index case who fulfills modified Simon-Broome criteria for FH (pretreatment LDL-C >95th percentile for age and sex, with (1) tendon xanthoma (proband or first-degree relative) or (2) either first-degree relative with premature CHD (<55 years of age in men or 65 years of age in women) or pretreatment LDL-C >95th percentile for age and sex) from Dallas, TX, USA (Ahmad et al, 2011) (PMID: 23064986); 1 index case who fulfils Simon-Broome criteria from MRC Clinical Sciences Centre, London UK (Tosi et al, 2007)(PMID: 17094996); and 1 index case with clinical diagnosis of FH (based on (1) a plasma LDL cholesterol concentration above the 95th percentile for age and sex and (2) the presence of xanthoma or coronary heart disease in the proband or at least one first degree relative with type IIa hypercholesterolemia, xanthoma, or CVD) from France (Amsellem et al, 2002) (PMID: 12436241), so PP4 is Met.

PP3

REVEL = 0.883. It is above 0.75, so PP3 is Met.

PP1_Strong

Variant segregates with FH phenotype in at least 6 informative meiosis from 3 families from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation): 6 affected family members have the variant, so PP1_Strong is Met.

PM2

PopMax MAF = 0.0001203 (0.01203%) in African/African American genomes (gnomAD v2.1.1), so PM2 is Met.

PM3

Variant meets PM2 and is identified in an index case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with homozygous FH phenotype (14.9 mmol/L) and LDLR c.761A>C/p.(Gln254Pro), classified as Likely pathogenic by these guidelines, in trans, so PM3 is Met.

PVS1

Variant is missense, so PVS1 is Not Met.

BS2

Not observed in 100 normolipidemic individuals from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation), so BS2 is Not Met.

BS4

None non-segregations reported, so BS4 is Not Met.

BS3

BS1

FAF = 0.00004089 (0.004089%) in African/African American genomes (gnomAD v2.1.1), so BS1 is Not Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

The index case has homozygous FH phenotype (14.9 mmol/L), so BP2 is Not Met.

BP4

REVEL = 0.883. It is not below 0.50, so BP4 is Not Met.

PS2

No evidence added, so PS2 is Not Met.

PS1

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

BA1

FAF = 0.00004089 (0.004089%) in African/African American genomes (gnomAD v2.1.1), so BA1 is Not Met.

PM6

No evidence added, so PM6 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.

PM5

4 other missense variants in the same codon: - NM_000527.5(LDLR):c.910G>C (p.Asp304His) (ClinVar ID 440612) - VUS 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 no variants in the same codon classified as Pathogenic by these guidelines, so PM5 is Not Met.

Approved on: 2021-12-17

Published on: 2022-04-05

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