Candidate missense mutations identified in the VWD3 3WINTERS-IPS cohort
| EU/IR . | VWF Gene Defect . | Domain (exon) . | SIFT . | Poly Phen-2 . | Mutation Taster . | CADD PHRED score . | ClinGen . | dbSNP(re) –HGMD (CM) . | First reported . | In vitro study . |
|---|---|---|---|---|---|---|---|---|---|---|
| IR | NM_000552.3: c.220G>A; p.Gly74Arg | D1 (3) | T | D | D | 33 | VUS | – | ||
| EU | NM_000552.3:c.449T>C; p.Leu150Pro | D1 (5) | D | D | D | 28 | LP† | rs61753994 | 63 * | |
| IR | NM_000552.3:c.498C>A; p.Asn166Lys | D1 (5) | D | D | D | 22.7 | VUS | – | ||
| EU/IR | NM_000552.3:c.823T>A; p.Cys275Ser | D1 (7) | D | D | D | 28.1 | LP | rs61753998 | 31 | 65 |
| IR | NM_000552.3:c.1574G>A; p.Gly525Glu | D2 (14) | D | D | D | 26.6 | VUS | – | ||
| EU | NM_000552.3:c.2311A>G; p.Met771Val | D' (18) | D | P | D | 23 | LP | rs1212894308 - CM061227 | 44 | |
| IR | NM_000552.3:c.2376C>G; p.Cys792Trp | D' (18) | D | D | D | 26.4 | LP | – | ||
| IR | NM_000552.3:c.2560C>T; p.Arg854Trp | D' (20) | D | D | D | 31 | LP | rs61748482 | 64 | 64 |
| EU | NM_000552.3:c.2771G>A; p.Arg924Gln | D3 (21) | T | B | N | 14.2 | LB† | rs33978901 | 47 | 53,57 |
| EU | NM_000552.3:c.3467C>T; p.Thr1156Met | D3 (26) | D | D | D | 26.2 | LP† | rs267607328 | 65 | 66 |
| EU | NM_000552.3:c.3568T>C; p.Cys1190Arg | D3 (27) | D | D | D | 27 | LP† | rs61749364 | 50 | 67 |
| EU | NM_000552.3:c.3679T>C; p.Cys1227Arg | D3 (28) | D | D | D | 28.7 | LP | rs61749366 | 68 | 67 |
| IR | NM_000552.3:c.4007G>A; p.Arg1336Gln‡ | A1 (28) | T | B | N | 21.8 | VUS† | rs886049741 | ||
| EU | NM_000552.3:c.5096C>T; p.Ser1699Phe | A3 (29) | D | D | D | 24.4 | VUS | – | 46 | |
| EU | NM_000552.3:c.5146G>A; p.Ala1716Thr | A3 (29) | T | B | D | 20.8 | VUS | CM115145 rs61750623 | ||
| IR | NM_000552.3:c.5429C>A; p.Ala1810Glu | A3 (31) | T | B | N | 7.8 | VUS | – | ||
| EU | NM_000552.3:c.5779T>C; p.Cys1927Arg | D4 (34) | D | D | D | 26.8 | VUS | CM930738 | 69 * | |
| IR | NM_000552.3:c.6520T>G; p.Cys2174Gly | D4 (37) | D | D | D | 27.1 | VUS | rs61750619 | 31 | |
| EU | NM_000552.3:c.6551G>C; p.Cys2184Ser | D4 (37) | D | D | D | 25.8 | LP | CM125355 | 36 * | 36 |
| EU | NM_000552.3:c.6634T>C; p.Cys2212Arg | D4 (38) | D | D | D | 29 | LP | CM125353 | 36 * | 36 |
| EU | NM_000552.3:c.6697G>A; p.Glu2233Lys | D4 (38) | D | D | D | 27.9 | VUS | rs61750623 | 46 | |
| EU | NM_000552.3:c.6847T>C; p.Cys2283Arg | C1 (39) | D | D | D | 28 | LP | CM137380 | 70 * | 70 |
| EU | NM_000552.3:c.6911G>A; p.Cys2304Tyr | C1 (40) | D | D | D | 24.7 | LP | rs61750626 | 49 | 71 |
| EU | NM_000552.3:c.6973T>A; p.Cys2325Ser | C1 (40) | D | D | D | 25.8 | LP | rs125608270 CM125358 | 36 * | 36 |
| EU | NM_000552.3:c.7085G>T; p.Cys2362Phe | C2 (42) | D | D | A | 27.6 | P† | rs61750630 | 72 * | 73 |
| EU | NM_000552.3:c.7182T>G; p.Cys2394Trp§ | C2 (42) | D | D | D | 21.9 | VUS | CM095418 | 32 * | |
| EU | NM_000552.3:c.7405T>C; p.Ser2469Pro | C3 (43) | T | P | N | 22.7 | VUS | rs61751287 | 49 * | |
| IR | NM_000552.3:c.7619T>A; p.Val2540Asp | C4 (45) | D | D | D | 27.9 | VUS | – | ||
| EU | NM_000552.3:c.7636A>T; p.Asn2546Tyr | C4 (45) | D | D | D | 32 | VUS | rs61751298 | 74 * | |
| EU | NM_000552.3:c.8012G>A; p.Cys2671Tyr§ | C6 (49) | D | D | D | 26.3 | LP | rs61751303 | 72 * | 75 |
| EU | NM_000552.3:c.8171G>A; p.Cys2724Tyr | CK (51) | D | D | D | 24.9 | VUS | – | ||
| EU | NM_000552.3:c.8216G>A; p.Cys2739Tyr | CK (51) | D | D | D | 26.6 | LP | rs61751305 | 76 | 75 |
| IR | NM_000552.3:c.8323T>C; p.Ser2775Pro | CK (52) | D | P | D | 23.1 | VUS | – |
| EU/IR . | VWF Gene Defect . | Domain (exon) . | SIFT . | Poly Phen-2 . | Mutation Taster . | CADD PHRED score . | ClinGen . | dbSNP(re) –HGMD (CM) . | First reported . | In vitro study . |
|---|---|---|---|---|---|---|---|---|---|---|
| IR | NM_000552.3: c.220G>A; p.Gly74Arg | D1 (3) | T | D | D | 33 | VUS | – | ||
| EU | NM_000552.3:c.449T>C; p.Leu150Pro | D1 (5) | D | D | D | 28 | LP† | rs61753994 | 63 * | |
| IR | NM_000552.3:c.498C>A; p.Asn166Lys | D1 (5) | D | D | D | 22.7 | VUS | – | ||
| EU/IR | NM_000552.3:c.823T>A; p.Cys275Ser | D1 (7) | D | D | D | 28.1 | LP | rs61753998 | 31 | 65 |
| IR | NM_000552.3:c.1574G>A; p.Gly525Glu | D2 (14) | D | D | D | 26.6 | VUS | – | ||
| EU | NM_000552.3:c.2311A>G; p.Met771Val | D' (18) | D | P | D | 23 | LP | rs1212894308 - CM061227 | 44 | |
| IR | NM_000552.3:c.2376C>G; p.Cys792Trp | D' (18) | D | D | D | 26.4 | LP | – | ||
| IR | NM_000552.3:c.2560C>T; p.Arg854Trp | D' (20) | D | D | D | 31 | LP | rs61748482 | 64 | 64 |
| EU | NM_000552.3:c.2771G>A; p.Arg924Gln | D3 (21) | T | B | N | 14.2 | LB† | rs33978901 | 47 | 53,57 |
| EU | NM_000552.3:c.3467C>T; p.Thr1156Met | D3 (26) | D | D | D | 26.2 | LP† | rs267607328 | 65 | 66 |
| EU | NM_000552.3:c.3568T>C; p.Cys1190Arg | D3 (27) | D | D | D | 27 | LP† | rs61749364 | 50 | 67 |
| EU | NM_000552.3:c.3679T>C; p.Cys1227Arg | D3 (28) | D | D | D | 28.7 | LP | rs61749366 | 68 | 67 |
| IR | NM_000552.3:c.4007G>A; p.Arg1336Gln‡ | A1 (28) | T | B | N | 21.8 | VUS† | rs886049741 | ||
| EU | NM_000552.3:c.5096C>T; p.Ser1699Phe | A3 (29) | D | D | D | 24.4 | VUS | – | 46 | |
| EU | NM_000552.3:c.5146G>A; p.Ala1716Thr | A3 (29) | T | B | D | 20.8 | VUS | CM115145 rs61750623 | ||
| IR | NM_000552.3:c.5429C>A; p.Ala1810Glu | A3 (31) | T | B | N | 7.8 | VUS | – | ||
| EU | NM_000552.3:c.5779T>C; p.Cys1927Arg | D4 (34) | D | D | D | 26.8 | VUS | CM930738 | 69 * | |
| IR | NM_000552.3:c.6520T>G; p.Cys2174Gly | D4 (37) | D | D | D | 27.1 | VUS | rs61750619 | 31 | |
| EU | NM_000552.3:c.6551G>C; p.Cys2184Ser | D4 (37) | D | D | D | 25.8 | LP | CM125355 | 36 * | 36 |
| EU | NM_000552.3:c.6634T>C; p.Cys2212Arg | D4 (38) | D | D | D | 29 | LP | CM125353 | 36 * | 36 |
| EU | NM_000552.3:c.6697G>A; p.Glu2233Lys | D4 (38) | D | D | D | 27.9 | VUS | rs61750623 | 46 | |
| EU | NM_000552.3:c.6847T>C; p.Cys2283Arg | C1 (39) | D | D | D | 28 | LP | CM137380 | 70 * | 70 |
| EU | NM_000552.3:c.6911G>A; p.Cys2304Tyr | C1 (40) | D | D | D | 24.7 | LP | rs61750626 | 49 | 71 |
| EU | NM_000552.3:c.6973T>A; p.Cys2325Ser | C1 (40) | D | D | D | 25.8 | LP | rs125608270 CM125358 | 36 * | 36 |
| EU | NM_000552.3:c.7085G>T; p.Cys2362Phe | C2 (42) | D | D | A | 27.6 | P† | rs61750630 | 72 * | 73 |
| EU | NM_000552.3:c.7182T>G; p.Cys2394Trp§ | C2 (42) | D | D | D | 21.9 | VUS | CM095418 | 32 * | |
| EU | NM_000552.3:c.7405T>C; p.Ser2469Pro | C3 (43) | T | P | N | 22.7 | VUS | rs61751287 | 49 * | |
| IR | NM_000552.3:c.7619T>A; p.Val2540Asp | C4 (45) | D | D | D | 27.9 | VUS | – | ||
| EU | NM_000552.3:c.7636A>T; p.Asn2546Tyr | C4 (45) | D | D | D | 32 | VUS | rs61751298 | 74 * | |
| EU | NM_000552.3:c.8012G>A; p.Cys2671Tyr§ | C6 (49) | D | D | D | 26.3 | LP | rs61751303 | 72 * | 75 |
| EU | NM_000552.3:c.8171G>A; p.Cys2724Tyr | CK (51) | D | D | D | 24.9 | VUS | – | ||
| EU | NM_000552.3:c.8216G>A; p.Cys2739Tyr | CK (51) | D | D | D | 26.6 | LP | rs61751305 | 76 | 75 |
| IR | NM_000552.3:c.8323T>C; p.Ser2775Pro | CK (52) | D | P | D | 23.1 | VUS | – |
Variants reported in bold are not listed in the EAHAD,17 HGMD,18 or Ensembl19 databases. Variants reported in italics have been identified in both European and Iranian populations. Underlined variants might affect normal splice site.
SIFT (Sorting Intolerant From Tolerant): T = tolerated; D = deleterious. PolyPhen-2: D = probably damaging; P = possibly damaging; B = benign. MutationTaster: D = disease causing; N = polymorphism; A = disease-causing automatic. ClinGen: P = pathogenic; LP = likely pathogenic; LB = likely benign; VUS = uncertain significance. In Combined Annotation-Dependent Depletion (CADD), a cutoff of 20 was used so that variants with score ≥20 were considered harmful.21
Indicates that the previous publication was concerning the same patient evaluated in this study.
Prediction already reported in ClinVar.
The pathogenicity of p.Arg1336Gln is unclear as it was found in the same allele together with c.2397_2400dupCATG, which implies that in this patient the p.Arg1336Gln does not play a role.
The second variants identified in this patient do not match the variant previously reported in the original publication of the patient.