Table 3.
Medically significant between-laboratory classification discrepancies in order of date identified
| Gene symbol | Variant (coding HGVS) | Variant (protein HGVS) | Disease area | Classificationsa | Number of days discrepant (as of 15th December, 2021) | Resolved classification | Upgrade/downgrade | Inter-laboratory discussion required | Reason for resolution |
|---|---|---|---|---|---|---|---|---|---|
| PROC | NM_000312.3: c.565C>T | NP_000303.1: p.(Arg189Trp) | MONDO: 0005570 hematologic disorder | P vs. VUS | 6 | LP | upgrade | no | review of ACMG/AMP criteria |
| CASR | NM_001178065.1: c.1212C>T | NP_001171536.1: p.(Val404=) | MONDO: 0005066 metabolic disease; MONDO: 0005151 endocrine system disorder | VUS vs. LB | 0 | LB | downgrade | no | review of ACMG/AMP criteria |
| COL4A3 | NM_000091.4: c.4421T>C | NP_000082.2: p.(Leu1474Pro) | MONDO: 0005240 kidney disorder | VUS vs. LB | 7 | VUS | upgrade | no | review of ACMG/AMP criteria |
| ABCA4 | NM_000350.2: c. 5693G>A | NP_000341.2: p.(Arg1898His) | MONDO: 0005283 retinal disorder | VUS vs. LB | 289 | LB | downgrade | yes | new functional evidence |
| FECH | NM_001012515.2: c. 333-48T>C; NM_000140.4: c.315-48T>C | NP_001012533.1:p.?; NP_000131.2: p.? | MONDO: 0005066 metabolic disease | P vs. VUS | 106 | P | upgrade | no | reduced penetrance variant (only pathogenic if found with another loss-of-function variant) |
| TGFBR1 | NM_004612.3: c.1468A>G | NP_004603.1: p.(Lys490Glu) | MONDO: 0004995 cardiovascular disorder | LP vs. VUSA | 183 | LP | upgrade | yes | additional segregation evidence provided by one laboratory |
| POLG | NM_002693.2: c.2890C>T | NP_002684.1: p.(Arg964Cys) | MONDO: 0004069 inborn mitochondrial metabolism disorder | LP vs. VUSA | 385 | continued discrepancy | N/A | yes | no resolution—reviewed extensively by mitochondrial experts; awaiting ClinGen expert panel review |
| POLG | NM_002693.2: c.2209G>C | NP_002684.1: p.(Gly737Arg) | MONDO: 0004069 inborn mitochondrial metabolism disorder | P vs. VUS | 0 | one classification withdrawn | N/A | no | out-of-date classification uploaded |
| MYH7 | NM_000257.2: c.532G>A | NP_000248.2: p.(Gly178Arg) | MONDO: 0004995 cardiovascular disorder | LP vs. VUS | 311 | ||||
| ABCA4 | NM_000350.2: c.71G>A | NP_000341.2: p.(Arg24His) | MONDO: 0005283 retinal disorder | LP vs. VUS | 270 | ||||
| NOD2 | NM_022162.2: c.566C>T | NP_071445.1: p.(Thr189Met) | MONDO: 0005046 immune system disorder | VUS vs. LB | 249 | ||||
| DSG2 | NM_001943.3: c.3036_3037insG | NP_001934.2: p.(Tyr1013ValfsTer25) | MONDO: 0004995 cardiovascular disorder | LP vs. VUSA | 58 | VUS | downgrade | yes | additional evidence from one laboratory and ClinVar |
| F8 | NM_000132.3: c.1094A>G | NP_000123.1: p.(Tyr365Cys) | MONDO: 0005570 hematologic disorder | LP vs. VUS | 222 | ||||
| HFE | NM_000410.3: c.187C>G | NP_000401.1: p.(His63Asp) | MONDO: 0005066 metabolic disease | P vs. VUS | 222 | ||||
| NIPBL | NM_133433.3: c.1178A>G | NP_597677.2: p.(Asn393Ser) | MONDO: 0019042 multiple congenital anomalies/dysmorphic syndrome | VUS vs. LB | 57 | LB | downgrade | yes | additional evidence from one laboratory and external public source |
| CASR | NM_000388.3: c.190A>G | NP_000379.2: p.(Asn64Asp) | MONDO: 0005066 metabolic disease; MONDO: 0005151 endocrine system disorder | LP vs. VUS | 0 | LP | upgrade | no | review of ACMG/AMP criteria |
| CFTR | NM_000492.3: c.2657+2_2657+3insA | NP_000483.3: p.? | MONDO: 0005087 respiratory system disorder | P vs. VUSA | 166 | ||||
| USH2A | NM_206933.2: c.4106C>T | NP_996816.2: p.(Ser1369Leu) | MONDO: 0005283 retinal disorder | P vs. VUS | 120 | ||||
| AHI1 | NM_001134831.1: c.2988delA | NP_001128303.1: p.(Val997SerfsTer20) | MONDO: 0019042 multiple congenital anomalies/dysmorphic syndrome | LP vs. VUS | 109 | ||||
| TNFRSF13B | NM_012452.2: c.310T>C | NP_036584.1: p.(Cys104Arg) | MONDO: 0005046 immune system disorder | P vs. VUS | 109 | ||||
| KMT2D | NM_003482.3: c.12862C>T | NP_003473.3: p.(Arg4288Trp) | MONDO: 0019042 multiple congenital anomalies/dysmorphic syndrome | VUS vs. LB | 103 | ||||
| CHEK2 | NM_007194.4: c.470T>C | NP_009125.1: p.(Ile157Thr) | MONDO: 0015356 hereditary neoplastic syndrome | LP vs. VUS | 6 | one classification withdrawn | N/A | no | variant reviewed as a risk factor and therefore doesn't align with ACMG/AMP classification criteria |
| CDH1 | NM_004360.4: c.387+5G>A | NP_004351.1: p.? | MONDO: 0015356 hereditary neoplastic syndrome | VUS vs. LB | 26 | ||||
| POLE | NM_006231.4: c.2090C>G | NP_006222.2: p.(Pro697Arg) | MONDO: 0015356 hereditary neoplastic syndrome | VUS vs. LB | 26 | ||||
| MSH6 | NM_000179.2: c.3226C>T | NP_000170.1: p.(Arg1076Cys) | MONDO: 0015356 hereditary neoplastic syndrome | LP vs. VUS | 9 | LP | upgrade | no | out-of-date classification uploaded |
| POLE | NM_006231.3: c.4523G>A | NP_006222.2: p.(Arg1508His) | MONDO: 0015356 hereditary neoplastic syndrome | VUS vs. LB | 23 | ||||
| BRCA2 | NM_000059.3: c.10076A>G | NP_000050.2: p.(Glu3359Gly) | MONDO: 0015356 hereditary neoplastic syndrome | VUS vs. LB | 23 | ||||
| MEFV | NM_000243.2: c.910G>A | NP_000234.1: p.(Gly304Arg) | MONDO: 0005046 immune system disorder | VUS vs. LB | 11 |
Medically significant classification discrepancies have been defined by Harrison et al. 2017.15
a
Pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), benign (B). VUSA is a variant of uncertain significance with suspected high clinical significance.