Variant: NM_001130987.2(DYSF):c.5620A>G (p.Met1874Val)

CA347223040

500678 (ClinVar)

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

UUID: 65a2ca65-4ef0-494e-9e88-b0ee9df56c8d

Approved on: 2025-06-10

Published on: 2025-07-08

HGVS expressions

NM_001130987.2:c.5620A>G
NM_001130987.2(DYSF):c.5620A>G (p.Met1874Val)
NC_000002.12:g.71669185A>G
CM000664.2:g.71669185A>G
NC_000002.11:g.71896315A>G
CM000664.1:g.71896315A>G
NC_000002.10:g.71749823A>G
NG_008694.1:g.220563A>G
ENST00000698057.1:c.3034A>G
ENST00000698058.1:c.2251A>G
ENST00000698059.1:c.2359A>G
ENST00000258104.8:c.5503A>G
ENST00000410020.8:c.5620A>G
ENST00000258104.7:c.5503A>G
ENST00000394120.6:c.5506A>G
ENST00000409366.5:c.5569A>G
ENST00000409582.7:c.5617A>G
ENST00000409651.5:c.5599A>G
ENST00000409744.5:c.5527A>G
ENST00000409762.5:c.5554A>G
ENST00000410020.7:c.5620A>G
ENST00000410041.1:c.5557A>G
ENST00000413539.6:c.5596A>G
ENST00000429174.6:c.5566A>G
ENST00000479049.6:n.2388A>G
NM_001130455.1:c.5506A>G
NM_001130976.1:c.5461A>G
NM_001130977.1:c.5524A>G
NM_001130978.1:c.5566A>G
NM_001130979.1:c.5596A>G
NM_001130980.1:c.5554A>G
NM_001130981.1:c.5617A>G
NM_001130982.1:c.5599A>G
NM_001130983.1:c.5569A>G
NM_001130984.1:c.5527A>G
NM_001130985.1:c.5557A>G
NM_001130986.1:c.5464A>G
NM_001130987.1:c.5620A>G
NM_003494.3:c.5503A>G
NM_001130455.2:c.5506A>G
NM_001130976.2:c.5461A>G
NM_001130977.2:c.5524A>G
NM_001130978.2:c.5566A>G
NM_001130979.2:c.5596A>G
NM_001130980.2:c.5554A>G
NM_001130981.2:c.5617A>G
NM_001130982.2:c.5599A>G
NM_001130983.2:c.5569A>G
NM_001130984.2:c.5527A>G
NM_001130985.2:c.5557A>G
NM_001130986.2:c.5464A>G
NM_003494.4:c.5503A>G

Pathogenic

• Met criteria codes: PM3_Supporting PVS1 PP4_Strong PM2_Supporting

• Not Met criteria codes: PP1

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.5503A>G variant in DYSF, which is also known as NM_001130987.2: c.5620A>G p.(Met1874Val), is a missense variant predicted to cause substitution of methionine by valine at amino acid 1835, p.(Met1835Val). This variant is also predicted to disrupt the splice donor site of exon 49 and strengthen an alternative donor site (SpliceAI score of 0.73 and 0.86, respectively). RNAseq analysis has demonstrated use of the cryptic splice site that results in the deletion of 23 bp of exon 49, leading to a frameshift and premature truncation, p.Met1835LeufsTer6, with nonsense mediated decay expected (PMID: 36983702; PVS1_RNA). This variant has been reported in at least two individuals with features consistent with LGMD (PMID: 30564623, 36983702, 32528171; LOVD Individuals #00314263, #00222598), including in unknown phase with a pathogenic variant in one patient (NM_003494.4: c.1639-6T>A, 0.5 pts, PMID: 30564623, 36983702; LOVD Individual #00222598) (PM3_Supporting). At least one individual with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in skeletal muscle and blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 36983702; PP4_Strong). The same two DYSF variants were identified in one affected family member, but phase was not determined (PMID: 36983702; PP1 not met). 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; 06/10/2025): PVS1_RNA, PM3_Supporting, PP4_Strong, PM2_Supporting.

Met criteria codes

• PM3_Supporting: This variant has been reported in at least two individuals with features consistent with LGMD (PMID: 30564623, 36983702, 32528171; LOVD Individuals #00314263, #00222598), including in unknown phase with a pathogenic variant in one patient (NM_003494.4: c.1639-6T>A, 0.5 pts, PMID: 30564623, 36983702; LOVD Individual #00222598) (PM3_Supporting). c.1639-6T>A is independently classified as P, cannot check co-occurrence
• PVS1: The NM_003494.4: c.5503A>G variant in DYSF, which is also known as NM_001130987.2: c.5620A>G p.(Met1874Val), is a missense variant predicted to cause substitution of methionine by valine at amino acid 1835, p.(Met1835Val). This variant is also predicted to disrupt the splice donor site of exon 49 and strengthen an alternative donor site (SpliceAI score of 0.73 and 0.86, respectively). RNAseq analysis has demonstrated use of the cryptic splice site that results in the deletion of 23 bp of exon 49, leading to a frameshift and premature truncation, p.Met1835LeufsTer6, with nonsense mediated decay expected (PMID: 36983702; PVS1_RNA).
• PP4_Strong: At least one individual with this variant and a second presumed diagnostic DYSF variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression in skeletal muscle and blood monoctyes, which is highly specific for DYSF-related LGMD (PMID: 36983702; PP4_Strong).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

Not Met criteria codes

• PP1: The same two DYSF variants were identified in one affected family member, but phase was not determined (PMID: 36983702).