The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_001130987.2(DYSF):c.4076T>C (p.Leu1359Pro)

CA1706888

555968 (ClinVar)

Gene: DYSF
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
UUID: a51ce6ee-f1c0-4429-8f6a-e5afdb1aa915
Approved on: 2025-01-08
Published on: 2025-01-08

HGVS expressions

NM_001130987.2:c.4076T>C
NM_001130987.2(DYSF):c.4076T>C (p.Leu1359Pro)
NC_000002.12:g.71611481T>C
CM000664.2:g.71611481T>C
NC_000002.11:g.71838611T>C
CM000664.1:g.71838611T>C
NC_000002.10:g.71692119T>C
NG_008694.1:g.162859T>C
ENST00000698057.1:c.1490T>C
ENST00000698058.1:c.707T>C
ENST00000698059.1:c.665T>C
ENST00000258104.8:c.4022T>C
ENST00000410020.8:c.4076T>C
ENST00000258104.7:c.4022T>C
ENST00000394120.6:c.4025T>C
ENST00000409366.5:c.4025T>C
ENST00000409582.7:c.4073T>C
ENST00000409651.5:c.4118T>C
ENST00000409744.5:c.3983T>C
ENST00000409762.5:c.4073T>C
ENST00000410020.7:c.4076T>C
ENST00000410041.1:c.4076T>C
ENST00000413539.6:c.4115T>C
ENST00000429174.6:c.4022T>C
ENST00000468173.1:n.258T>C
ENST00000472873.5:n.406T>C
ENST00000479049.6:n.907T>C
ENST00000487180.5:n.241T>C
ENST00000494501.5:n.366-46T>C
NM_001130455.1:c.4025T>C
NM_001130976.1:c.3980T>C
NM_001130977.1:c.3980T>C
NM_001130978.1:c.4022T>C
NM_001130979.1:c.4115T>C
NM_001130980.1:c.4073T>C
NM_001130981.1:c.4073T>C
NM_001130982.1:c.4118T>C
NM_001130983.1:c.4025T>C
NM_001130984.1:c.3983T>C
NM_001130985.1:c.4076T>C
NM_001130986.1:c.3983T>C
NM_001130987.1:c.4076T>C
NM_003494.3:c.4022T>C
NM_001130455.2:c.4025T>C
NM_001130976.2:c.3980T>C
NM_001130977.2:c.3980T>C
NM_001130978.2:c.4022T>C
NM_001130979.2:c.4115T>C
NM_001130980.2:c.4073T>C
NM_001130981.2:c.4073T>C
NM_001130982.2:c.4118T>C
NM_001130983.2:c.4025T>C
NM_001130984.2:c.3983T>C
NM_001130985.2:c.4076T>C
NM_001130986.2:c.3983T>C
NM_003494.4:c.4022T>C
More

Pathogenic

Met criteria codes 5
PM3 PP4_Strong PS3 PP1 PP3
Not Met criteria codes 1
PM2

Evidence Links 3

Expert Panel

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

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Limb Girdle Muscular Dystrophy VCEP
The NM_003494.4: c.4022T>C variant in DYSF, which is also known as NM_001130987.2: c.4076T>C p.(Leu1359Pro), is a missense variant predicted to cause substitution of leucine by proline at amino acid 1341 (p.Leu1341Pro). This variant has been detected in a homozygous state in at least seven individuals with clinical signs of limb girdle muscular dystrophy (1.0 pt, PMID: 16705711, 19528035, 22057634, 26436962, 27647186, 28403181, 34559919, 34624274) (PM3). It has also been observed in trans with a nonsense variant, c.4228C>T p.(Gln1410Ter), in one affected individual (PMID: 34624274). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 16705711, 21522182). The variant was also reported to co-segregate with the disease in six affected family members from three families (PMID: 16705711, 21522182, 34624274) (PP1, capped with PP4_Strong). The filtering allele frequency of the variants is 0.0003434 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 5/30616), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141) (PS3). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). The computational predictor REVEL gives a score of 0.89, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). 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; 01/08/2025): PM3, PP4_Strong, PP1, PS3, PP3.
Met criteria codes
PM3
This variant has been detected in a homozygous state in at least seven individuals with limb girdle muscular dystrophy (1.0 pt, PMID: 16705711, 19528035, 22057634, 26436962, 27647186, 28403181, 34559919, 34624274) (PM3). It has also been observed in trans with a nonsense variant, c.4228C>T p.(Gln1410Ter), in one affected individual (PMID: 34624274).
PP4_Strong
At least one patient with this variant displayed progressive limb-girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 16705711, 21522182).
PS3
Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3)

PP1
The variant was also reported to co-segregate with the disease in six affected family members from three families (PMID: 16705711, 21522182, 34624274) (PP1). (capped with PP4_Strong)
PP3
The computational predictor REVEL gives a score of 0.89, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3).
Not Met criteria codes
PM2
The filtering allele frequency of the variants is 0.0003434 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 5/30616), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met).
Curation History
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