Table 1. Comparison of assignment of variant pathogenicity among submitters to DNA variation databases and among expert reviewers.
| Sequencing data | Clinical characteristics | Variant databases and Literature | Expert review | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| # | rsID | cDNA position | Amino acid change | GVS function | DLCNC | Max LDL-Ca | MAF, % | In-silico analyses | ClinVar | Reports | #1 | #2 |
| 1 | rs758194385 | c.1691A>G | p.(Asn564Ser) | Missense | 2 | 4.7 | 0.05 | LP | LP [1] | P | LP | LP |
| 2 | rs144614838 | c.1432G>A | p.(Gly478Arg) | Missense | 3 | 6.4 | 0.05 | LP | P; LP; VUS [1] | VUS | LP | LP |
| 3 | rs137853962 | c.1875C>T | p.(Asn625=) | Synonymous | 0 | 3.6 | 0.05 | LB | LB [1] | LB | LB | LB |
| 4 | rs137853960 | c.148G>T | p.(Ala50Ser) | Missense | 0 | 3.1 | 0.05 | LB | B/VUS [1] | VUS | LB | LB |
| 5 | rs148698650 | c.829G>A | p.(Glu277Lys) | Missense | 1 | 4.0 | 0.05 | VUS | B/LB [2] | B | LB | LB |
| 6 | rs368562025 | c.1238C>T | p.(Thr413Met) | Missense | 1 | 4.0 | 0.05 | LP | P, LP, VUS [1] | VUS | VUS | VUS |
| 7 | rs150673992 | c.757C>T | p.(Arg253Trp) | Missense | 1 | 2.6 | 0.05 | LP | LP, VUS, LB [1] | LB/B | VUS | VUS |
| 8 | rs200142970 | c.2252G>A | p.(Arg751Gln) | Missense | 1 | 4.8 | 0.05 | LB | LB, VUS [1] | VUS | VUS | VUS |
| 9 | rs148181903 | c.1837G>A | p.(Val613Ile) | Missense | 0 | 3.4 | 0.05 | LB | LB, VUS [1] | VUS | LB | LB |
| 10 | rs139089530 | c.508G>A | p.(Asp170Asn) | Missense | 2 | 4.6 | 0.05 | LP | VUS [1] | — | VUS | VUS |
| 11 | rs143992984 | c.806G>A | p.(Gly269Asp) | Missense | 1 | 3.9 | 0.05 | LP | LB, VUS [1] | VUS/B | LB | LB |
| 12 | rs146354103 | c.507C>T | p.(Asn169Asn) | Synonymous | 1 | 4.8 | 0.05 | LB | B/LB [2] | — | VUS | VUS |
| 13 | rs143872778 | c.1836C>T | p.(Ala612=) | Synonymous | 1 | 4.3 | 0.05 | LB | LB [1] | — | VUS | VUS |
| 14 | rs116405216 | c.941-4G>A | — | Splice region | 0 | 3.5 | 0.01 | LP | LB [2] | P | VUS | VUS |
| 15 | rs138315511 | c.1085A>C1 | p.(Asp362Ala) | Missense | 1 | 3.8 | 0.10 | LP | LP, LB [1] | P, LB | VUS | VUS |
| 16 | rs147509697 | c.58G>A | p.(Gly20Arg) | Missense | 0 | 3.8 | 0.10 | LB | LB, VUS [1] | P, VUS, B | LB | LB |
| 17 | rs13306498 | c.1194C>T | p.(Ile398=) | Synonymous | 2 | 2.5 | 0.15 | LB | B [1] | B | LB | LB |
| 18 | rs137853963 | c.2231G>A | p.(Arg744Gln) | Missense | 2 | 3.9 | 0.10 | LB | LB, LP [1] | LP, B | LB | LB |
| 19 | rs11669576 | c.1171G>A | p.(Ala391Thr) | Missense | 4 | 3.3 | 3.95 | LB | B [1] | — | LB | LB |
| 20 | rs12710260 | c.1060+10G>C | — | Intron | 0 | 3.0 | 0.05 | LB | B [2] | — | LB | LB |
| 21 | rs17248882 | c.1706-10G>A | — | Intron | 2 | 4.2 | 0.01 | LB | B, LB, VUS [1] | — | VUS | VUS |
| 22 | rs45508991 | c.2177C>T | p.(Thr726Ile) | Missense | 2 | 3.8 | 0.94 | LP | B/LB/VUS [1] | B | LB | LB |
| 23 | rs5926 | c.1959T>C | p.(Val653Val) | Synonymous | 2 | 3.1 | 0.30 | LB | B [2] | B | LB | LB |
| 24 | rs72658861 | c.1061-8T>C | — | Splice region | 0 | 3.2 | 0.05 | LB | B/LB/VUS [1] | B | LB | LB |
| 25 | rs72658867 | c.2140+5G>A | — | Splice region | 0 | 3.0 | 0.05 | VUS | LB/VUS [1] | B | LB | LB |
Abbreviations: B, benign; DLCNC, Dutch Lipid Clinic Network Criteria 19,26 LDL-C, low-density lipoprotein cholesterol; LB, likely benign; LP, likely pathogenic; MAF, minor allele frequency; P, pathogenic; VUS, variant of uncertain significance.
LDL-C levels are given in mmol/L.
The NCBI-ClinVar database's levels of evidence: 0 – no assert criteria or clinical significance not provided; 1 – single source with criteria provided; 2 – multi-source consistency; 3 – expert panel; 4 – based on practice guidelines of ACMG, CPIC. Reference sequence: NM_000527.4, NP_000518.1, NG_009060.1, LRG_274.
Highlighted in bold are LDLR variants identified as likely pathogenic and reportable based on final expert review and consensus.
Five variants (c.1691A>G, c.941-4G>A4, c.1085A>C2, c.58G>A and c.1194C>T) were reported at least once in the literature either in the disease setting, as part of FH case descriptions or FH registry analysis. Supplementary Table 3 summarizes the analysis of the original contributions categorizing variants reported herein, including incidental findings in whole-exome sequencing of ACMG genes.