Variant: NM_001130987.2(DYSF):c.5003+1249G>T

CA10603819

281197 (ClinVar)

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: 29e5fb14-c3da-4b11-a5cd-6aeddbad610d

Approved on: 2025-04-23

Published on: 2025-05-16

HGVS expressions

NM_001130987.2:c.5003+1249G>T
NM_001130987.2(DYSF):c.5003+1249G>T
NC_000002.12:g.71661900G>T
CM000664.2:g.71661900G>T
NC_000002.11:g.71889030G>T
CM000664.1:g.71889030G>T
NC_000002.10:g.71742538G>T
NG_008694.1:g.213278G>T
ENST00000698057.1:c.2417+1249G>T
ENST00000698058.1:c.1634+1249G>T
ENST00000698059.1:c.1742+1249G>T
ENST00000258104.8:c.4886+1249G>T
ENST00000410020.8:c.5003+1249G>T
ENST00000258104.7:c.4886+1249G>T
ENST00000394120.6:c.4889+1249G>T
ENST00000409366.5:c.4952+1249G>T
ENST00000409582.7:c.5000+1249G>T
ENST00000409651.5:c.4982+1249G>T
ENST00000409744.5:c.4910+1249G>T
ENST00000409762.5:c.4937+1249G>T
ENST00000410020.7:c.5003+1249G>T
ENST00000410041.1:c.4940+1249G>T
ENST00000413539.6:c.4979+1249G>T
ENST00000429174.6:c.4949+1249G>T
ENST00000479049.6:n.1771+1249G>T
NM_001130455.1:c.4889+1249G>T
NM_001130976.1:c.4844+1249G>T
NM_001130977.1:c.4907+1249G>T
NM_001130978.1:c.4949+1249G>T
NM_001130979.1:c.4979+1249G>T
NM_001130980.1:c.4937+1249G>T
NM_001130981.1:c.5000+1249G>T
NM_001130982.1:c.4982+1249G>T
NM_001130983.1:c.4952+1249G>T
NM_001130984.1:c.4910+1249G>T
NM_001130985.1:c.4940+1249G>T
NM_001130986.1:c.4847+1249G>T
NM_001130987.1:c.5003+1249G>T
NM_003494.3:c.4886+1249G>T
NM_001130455.2:c.4889+1249G>T
NM_001130976.2:c.4844+1249G>T
NM_001130977.2:c.4907+1249G>T
NM_001130978.2:c.4949+1249G>T
NM_001130979.2:c.4979+1249G>T
NM_001130980.2:c.4937+1249G>T
NM_001130981.2:c.5000+1249G>T
NM_001130982.2:c.4982+1249G>T
NM_001130983.2:c.4952+1249G>T
NM_001130984.2:c.4910+1249G>T
NM_001130985.2:c.4940+1249G>T
NM_001130986.2:c.4847+1249G>T
NM_003494.4:c.4886+1249G>T

Pathogenic

• Met criteria codes: PM3_Strong PP1 PM2_Supporting PVS1_Moderate PP4_Strong

• Not Met criteria codes: PS3 PM4

Expert Panel

Limb Girdle Muscular Dystrophy VCEP

Criteria Specification Information

Criteria Specification: ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DYSF Version 1.0.0

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_003494.4: c.4886+1249G>T variant in DYSF, which is also known as NM_001130987.2: c.5003+1249G>T, is a deep intronic variant. SpliceAI gives a score of 0.26 for donor gain and 0.12 for acceptor gain. RNAseq analysis has demonstrated two splice effects of this variant: activation of a cryptic splice site within DYSF intron 44 that leads to the insertion of 177 bp intronic sequence and a non-frameshifting insertion of 59 amino acids, p.Lys1646_Met1647ins59; and activation of a cryptic splice site within DYSF intron 44 that leads to the insertion of 88 bp of intronic sequence and a frameshift with nonsense mediated decay expected, p.Lys1646AsnfsTer13 (PMID: 36983702; PVS1_Moderate_RNA). This variant has been reported in at least four individuals with features consistent with LGMD (PMID: 26273692, 36983702, 30564623, 25493284), including confirmed in trans with a likely pathogenic or pathogenic variant in one patient (NM_003494.4: c.1168G>A p.(Asp390Asn), 1.0 pt, PMID: 26273692) and in unknown phase with a pathogenic variant in two patients (NM_003494.4: c.857T>A p.(Val286Glu), 0.5 pts, PMID: 36983702, 30564623, 25493284; NM_003494.4: c.1834C>T p.(Gln612Ter), 0.5 pts, PMID: 25493284) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in DYSF showed progressive muscle weakness and absent dysferlin protein expression in skeletal muscle and/or blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 36983702, 25493284; PP4_Strong). In addition, this variant has been shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 30564623, 30564623) (PP1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/23/2025): PVS1_Moderate_RNA, PM3_Strong, PP4_Strong, PP1, PM2_Supporting.

Met criteria codes

• PM3_Strong: This variant has been reported in at least four individuals with features consistent with LGMD (PMID: 26273692; PMID: 36983702; PMID: 30564623; PMID: 25493284), including confirmed in trans with a likely pathogenic or pathogenic variant in one patient (c.1168G>A p.(Asp390Asn), 1.0 pt, PMID: 26273692) and in unknown phase with a pathogenic variant in two patients (c.857T>A p.(Val286Glu), 0.5 pts, PMID: 36983702; PMID: 30564623; PMID: 25493284; c.1834C>T p.(Gln612Ter), 0.5 pts, PMID: 25493284) (PM3_Strong).
• PP1: This variant has been reported to co-segregate with the LGMD phenotype in one affected family member (PMID: 30564623; PMID: 30564623) (PP1).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• PVS1_Moderate: The NM_003494.4: c.4886+1249G>T variant, which is also known as NM_001130987.2: c.5003+1249G>T, is a deep intronic variant. SpliceAI gives a score of 0.26 for donor gain and 0.12 for acceptor gain. RNAseq analysis has demonstrated two splice effects of this variant: activation of a cryptic splice site within DYSF intron 44 that leads to the insertion of 177 bp intronic sequence and a non-frameshifting insertion of 59 amino acids, p.Lys1646_Met1647ins59; and activation of a cryptic splice site within DYSF intron 44 that leads to the insertion of 88 bp of intronic sequence and a frameshift with nonsense mediated decay expected, p.Lys1646AsnfsTer13 (PMID: 36983702; PVS1_Moderate_RNA). PVS1_Moderate discussed and approved by VCEP on 05/28/2024
• PP4_Strong: At least one patient with this variant and a second presumed diagnostic variant in DYSF showed progressive muscle weakness and absent dysferlin protein expression in skeletal muscle and/or blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 36983702; PMID: 25493284; PP4_Strong).

Not Met criteria codes

• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline