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. 2024 Mar 1;56(3):395–407. doi: 10.1038/s41588-023-01651-0

Table 1.

Genetic details of the patients with SRPK3/TTN myopathy

Fam SRPK3 variants TTN variants
cDNA change Protein change Exon Predicted effect (CADD score) gnomAD freq. cDNA change Protein change Exon Band Predicted effect (CADD score) gnomAD freq. Previously reported
A c.1519+1G>A p.? in 14 Splice-donor site Absent c.98810_98811del p.Lys32937Argfs*5 354 A-band Frameshift Absent No
B c.735dupC p.Ser246Leufs*17 7 Frameshift Absent c.93166C>T p.Arg31056* 340 A-band Stop gain 1/248,360 LOVD
C c.1144+1G>A p.Asp284_Thr383delinsAla in 10 Splice-donor site Absent c.95708G>A p.Cys31903Tyr 345 A-band Missense (24.6) Absent

No

No
c.19234C>G p.Pro6412Ala 67 I-band Missense (20.5) Absent
D c.387+2_387+3delTG p.? 4 Splice site Absent c.25480C>T p.Arg8494* 89 I-band Stop gain Absent Ref. 38
E c.475C>T p.His159Tyr 5 Splice site Absent c.57168_57169insT p.Ala19057Cysfs*6 294 A-band Frameshift Absent No
F c.1301T>A p.Val434Glu 12 Missense (24.6) Absent c.39226A>T p.Lys13076* 205 I-band Stop gain Absent No
G c.1333G>A p.Asp445Asn 12 Missense (25.1) Absent c.101440del p.Glu33814Asnfs*7 358 M-line Frameshift Absent No
H c.1289G>A p.Arg430Gln 12 Missense (25.7) Absent c.38919del p.Leu12974Trpfs*104 201a N/a Frameshift 1/31,156 No
J c.388-2A>G p.? in 4 Splice-acceptor site Absent c.37017del p.Lys12339Asnfs*608 178a N/a Frameshift Absent No
K c.1657C>T p.Arg553Trp 15 Missense (29.1) 1/181,513b c.66699T>G p.Tyr22233* 317 A-band Stop gain Absent No
L c.190+2T>C p.? 2 Donor splice site Absent c.24019C>T p.Arg8007* 84 I-band Stop gain Absent No
M c.1213_1218del p.Lys405_Ile406del 11 Inframe Absent c.86413_86416delinsATG p.Asp28805Metfs*6 326 A-band Frameshift Absent No
N c.260G>A p.Trp87* 3 Stop gain Absent c.95008C>T p.Arg31670* 342 A-band Stop gain 1/248,798 No
O c.1070_1073del p.Phe358Leufs*24 10 Frameshift Absent c.103420C>T p.Gln34474* 358 M-line Stop gain Absent No
P c.749-2A>G p.? in 7 Splice-acceptor site Absent c.104092del p.Arg34698Glufs*49 358 M-line Frameshift Absent No
Q c.1363G>A p.Glu455Lys 13 Missense (28) 1/178,034b c.77610del p.Thr25871Glnfs*16 326 A-band Frameshift Absent No
R c.1236delC p.Asn412Lysfs*24 11 Frameshift Absent c.89766G>C p.Lys29922Asn 336 A-band Missense (22.9) Absent No
S c.774+5G>C p.? in 8 Splice site Absent c.91085_91088del p.Glu30362Glyfs*28 336 A-band Frameshift Absent No
T c.804_807del p.Lys269Argfs*2 9 Frameshift Absent c.104947C>T p.Gln34983* 358 M-line Stop gain Absent No
U c.587T>C p.Leu196Pro 7 Missense (23.1) Absent c.24897del p.Glu8300Asnfs*22 87 I-band Frameshift Absent No
V c.392G>C p.Arg131Pro 5 Missense (25.4) Absent c.76821C>A p.Asn25607Lys 327 A-band Missense (21.3) Absent No
c.404C>A p.Pro135His Missense (28.7) Absent c.53938G>C p.Ala17980Pro 281 A-band Missense (23) Absent No
W c.749-2A>C p.? in 7 Splice-acceptor site Absent c.106259_106271del p.Pro35420Leufs*54 359 M-line Frameshift Absent No
X c.469G>A p.Gly157Arg 5 Missense (45) Absent c.24087del p.Lys8030Asnfs*13 84 I-band Frameshift Absent No
Y c.1245G>A p.Trp415* 11 Stop gain Absent c.70289T>A p.Val23430Asp 327 A-band Missense (23.5) Absent No
Z c.1035dupC p.Ala346Argfs*37 10 Frameshift Absent c.48283C>T p.Arg16095* 258 A-band Stop gain 1/119,862 Ref. 19

All variants are reported according to the HGVS recommendations (http://varnomen.hgvs.org/). Genomic coordinates are based on GRCh37/hg19 assembly. CADD scores were calculated for missense changes only. Freq. indicates frequency within the largest available control population (gnomAD, https://gnomad.broadinstitute.org/). SRPK3 variants are annotated based on ENSG00000184343.6, NM_014370 .3, transcript ENST00000370101.3 and NP_055185.2. TTN variants are annotated based on NG 011618.3 or LRG 391 and inferred-complete transcript variant-IC (NM 001267550.1 or ENST00000589042.5) and NP_001254479.1. TTN exon numbering is the LRG numbering (Leiden Open Variation Database, http://www.LOVD.nl/TTN). TITINdb was used to map the TTN variants to titin domains (http://fraternalilab.kcl.ac.uk/TITINdb).

aMeta-transcript only exons, thought to be highly expressed during fetal development5. No missense variants in exons 344 or 364, known to be associated with HMERF and TMD, both dominant skeletal titinopathies (OMIM 603689 and 600334, respectively) were found. CADD scores for missense variants predicted them to be among the 0.005–0.00003% most damaging variants in the genome.

bThe SRPK3 p.Glu455Lys variant is found once in the control population in a healthy female carrier, whereas the SRPK3 c.1657C>T; p.Arg553Trp variant is found in a healthy male, who on manual inspection does not carry a TTN truncating variant.

HGVS, Human Genome Variation Society; in, intron.