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.233G>A (p.Arg78His)

CA042534

251085 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 8be0642c-9230-4c24-9637-a26525d228e6

HGVS expressions

NM_000527.5:c.233G>A

NM_000527.5(LDLR):c.233G>A (p.Arg78His)

NC_000019.10:g.11102706G>A

CM000681.2:g.11102706G>A

NC_000019.9:g.11213382G>A

CM000681.1:g.11213382G>A

NC_000019.8:g.11074382G>A

NG_009060.1:g.18326G>A

ENST00000558518.6:c.233G>A

ENST00000252444.9:n.487G>A

ENST00000455727.6:c.233G>A

ENST00000535915.5:c.190+2361G>A

ENST00000545707.5:c.233G>A

ENST00000557933.5:c.233G>A

ENST00000557958.1:n.319G>A

ENST00000558013.5:c.233G>A

ENST00000558518.5:c.233G>A

NM_000527.4:c.233G>A

NM_001195798.1:c.233G>A

NM_001195799.1:c.190+2361G>A

NM_001195800.1:c.233G>A

NM_001195803.1:c.233G>A

NM_001195798.2:c.233G>A

NM_001195799.2:c.190+2361G>A

NM_001195800.2:c.233G>A

NM_001195803.2:c.233G>A

Uncertain Significance

PP4 PP3 PM2 PS4_Supporting

PS2 PS3 PS1 PP1 PP2 PM6 PM3 PM1 PM4 PM5 BA1 BS2 PVS1 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1

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.233G>A (p.Arg78His) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS4_Supporting and PP4 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: PM2 - PopMax MAF = 0.0001202 (0.012%) in African/African American exomes+genomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met. PP3 - REVEL = 0.806. It is above 0.75, so PP3 is met. PS4_supporting - variant meets PM2 and was identified in: - 1 index case with SB criteria of FH from PMID 31993549 (Garg et al., 2019), North America; - 1 index case with DLCN at least 8 (TC>10mmol/L and xanthomas) from PMID 27830735 (Jiang et al. 2016), China; - 1 index case with MEDPED criteria of FH from Benyahya et al. (2010) (paper cited in HGMD), Morocco; 3 unrelated index cases, so PS4_Supporting is met. PP4 - variant meets PM2 and was identified in 3 unrelated index cases who fulfill clinical criteria for FH after alternative causes of high cholesterol were excluded (please see PS4 for details), so PP4 is met.

PP4

variant meets PM2 and was identified in: - 1 index case with SB criteria of FH from PMID 31993549 (Garg et al., 2019), North America - 1 index case with DLCN at least 8 (TC>10mmol/L and xanthomas) from PMID 27830735 (Jiang et al. 2016), China - 1 index case with MEDPED criteria of FH from Benyahya et al. (2010) (paper cited in HGMD), Morocco so PP4 is met

PP3

REVEL = 0.806. It is above 0.75, so PP3 is met

PM2

PopMax MAF = 0.0001202 (0.012%) in African/African American exomes+genomes (gnomAD v2.1.1). It is below 0.02%, so PM2 is met

PS4_Supporting

PS2

no de novo occurrence

PS3

there are no functional studies performed in this variant

PS1

there is no other missense variant that leads to the same amino acid change, so not met

PP1

no segregation data

PP2

not applicable

PM6

no de novo occurrence

PM3

variant identified in 1 index case with also NM_000527.5(LDLR):c.1474G>A (p.Asp492Asn) and a LDL-C max of 400mg/dl from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) --- not clearly a heterozygous phenotype, so not met

PM1

variant is missense and meets PM2, but it is not on exon 4 and does not alter Cys, so not met

PM4

variant is missense, so not applicable

PM5

1 other missense variant in the same codon: NM_000527.5(LDLR):c.232C>T (p.Arg78Cys) - classified as VUS by the FH VCEP so PM5 is not met

BA1

FAF = 0.00006011 (0.006%) in European non-Finnish exomes (gnomAD v2.1.1). It is not above 0.5%, so not met

BS2

variant was not searched in normolipidemic individuals, so not met

PVS1

variant is missense and not in initiation codon, so not applicable

BS4

no segregation data

BS3

there are no functional studies performed in this variant

BS1

FAF = 0.00006011 (0.006%) in European non-Finnish exomes (gnomAD v2.1.1). It is not above 0.2%, so not met

BP5

not applicable

BP7

variant is missense, so not applicable

BP2

BP3

not applicable

BP4

REVEL = 0.806. It is not below 0.50, so BP4 is not met

BP1

not applicable

Approved on: 2022-08-28

Published on: 2022-08-28

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