Evidence Repository
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 label mismatch: DYSF vs undefined
  • 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.404C>T (p.Pro135Leu)

CA1705344

284579 (ClinVar)

Gene: DYSF
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 611e901d-b443-4b62-af27-656f95f2ebab
Approved on: 2025-06-17
Published on: 2025-07-08

HGVS expressions

NM_001130987.2:c.404C>T
NM_001130987.2(DYSF):c.404C>T (p.Pro135Leu)
NC_000002.12:g.71511865C>T
CM000664.2:g.71511865C>T
NC_000002.11:g.71738995C>T
CM000664.1:g.71738995C>T
NC_000002.10:g.71592503C>T
NG_008694.1:g.63243C>T
ENST00000258104.8:c.401C>T
ENST00000410020.8:c.404C>T
ENST00000258104.7:c.401C>T
ENST00000394120.6:c.404C>T
ENST00000409366.5:c.404C>T
ENST00000409582.7:c.401C>T
ENST00000409651.5:c.404C>T
ENST00000409744.5:c.404C>T
ENST00000409762.5:c.401C>T
ENST00000410020.7:c.404C>T
ENST00000410041.1:c.404C>T
ENST00000413539.6:c.401C>T
ENST00000429174.6:c.401C>T
NM_001130455.1:c.404C>T
NM_001130976.1:c.401C>T
NM_001130977.1:c.401C>T
NM_001130978.1:c.401C>T
NM_001130979.1:c.401C>T
NM_001130980.1:c.401C>T
NM_001130981.1:c.401C>T
NM_001130982.1:c.404C>T
NM_001130983.1:c.404C>T
NM_001130984.1:c.404C>T
NM_001130985.1:c.404C>T
NM_001130986.1:c.404C>T
NM_001130987.1:c.404C>T
NM_003494.3:c.401C>T
NM_001130455.2:c.404C>T
NM_001130976.2:c.401C>T
NM_001130977.2:c.401C>T
NM_001130978.2:c.401C>T
NM_001130979.2:c.401C>T
NM_001130980.2:c.401C>T
NM_001130981.2:c.401C>T
NM_001130982.2:c.404C>T
NM_001130983.2:c.404C>T
NM_001130984.2:c.404C>T
NM_001130985.2:c.404C>T
NM_001130986.2:c.404C>T
NM_003494.4:c.401C>T
More

Likely Benign

Met criteria codes 1
BP2
Not Met criteria codes 5
BP4 PP4 PM2 PM3 BS3

Evidence Links 0

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.401C>T variant in DYSF, which is also known as NM_001130987.2: c.404C>T p.(Pro135Leu), is a missense variant predicted to cause substitution of proline by leucine at amino acid 134, p.(Pro134Leu). This variant has been observed in two individuals with features consistent with LGMD (PMID: 36983702; 23406536; 30564623; LOVD Individual #00222735); however, in both cases it was identified in cis with a null variant, including one classified as pathogenic by the ClinGen LGMD VCEP (NM_003494.4: c.5022del p.(Phe1674LeufsTer48), PMID: 36983702) (BP2; PP4 and PM3 not applicable). The filtering allele frequency of this variant is 0.0001865 in gnomAD v4.1.0 genomes (the upper threshold of the 95% CI of 3/41580 African/African American chromosomes), which is greater than the ClinGen LGMD VCEP threshold for PM2_Supporting (≤0.0001) (PM2 not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed that the Pro134Leu protein reached the cell membrane, indicating no significant impact on this aspect of protein function (PMID: 35028538; BS3 not met). The computational predictor REVEL gives a score of 0.15, which is above the LGMD VCEP threshold of ≤0.1 for BP4 (criterion not met). In summary, this variant meets the criteria to be classified as Likely Benign 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; 06/17/2025): BP2.
Met criteria codes
BP2
This variant has been observed in cis with the variant NM_003494.4: c.5022del p.(Phe1674LeufsTer48), which is classified as pathogenic by the ClinGen LGMD VCEP (PMID: 36983702) (BP2). In 2nd patient, apparently in cis with c.502del p.(Asp168MetfsTer59), which has not been curated yet.
Not Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.15, which is above the LGMD VCEP threshold of ≤0.1 (BP4 not met).
PP4
While this variant has been observed in conjunction with a second DYSF variant in at least two patients with clinically suspected LGMD, this code was not applied given its occurrence in cis with a proven (classified by VCEP) or presumed (null variant not yet curated) pathogenic variant.
PM2
The filtering allele frequency of this variant is 0.0001865 (the upper threshold of the 95% CI of 3/41580 African/African American genome chromosomes) in gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2 not met).
PM3
While this variant has been observed in conjunction with a second DYSF variant in at least two patients with clinically suspected LGMD, this code was not applied given its occurrence in cis with a proven (classified by VCEP) or presumed (null variant not yet curated) pathogenic variant.
BS3
Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed that the Pro134Leu protein reached the cell membrane, indicating no significant impact on this aspect of protein function (PMID: 35028538).
Curation History
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