Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001130987.2(DYSF):c.850A>G (p.Thr284Ala)

CA347208767

813972 (ClinVar)

Gene: DYSF (HGNC:8291)

Condition: autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152)

Inheritance Mode: Autosomal recessive inheritance

UUID: 1ee75b3e-97ed-43dd-a4df-97a21dc4ca5e

Approved on: 2026-04-29

Published on: 2026-05-07

HGVS expressions

NM_001130987.2(DYSF):c.850A>G (p.Thr284Ala)

NM_001130987.2:c.850A>G

NC_000002.12:g.71515713A>G

CM000664.2:g.71515713A>G

NC_000002.11:g.71742843A>G

CM000664.1:g.71742843A>G

NC_000002.10:g.71596351A>G

NG_008694.1:g.67091A>G

ENST00000258104.8:c.754A>G

ENST00000410020.8:c.850A>G

ENST00000258104.7:c.754A>G

ENST00000394120.6:c.757A>G

ENST00000409366.5:c.757A>G

ENST00000409582.7:c.847A>G

ENST00000409651.5:c.850A>G

ENST00000409744.5:c.757A>G

ENST00000409762.5:c.847A>G

ENST00000410020.7:c.850A>G

ENST00000410041.1:c.850A>G

ENST00000413539.6:c.847A>G

ENST00000429174.6:c.754A>G

NM_001130455.1:c.757A>G

NM_001130976.1:c.754A>G

NM_001130977.1:c.754A>G

NM_001130978.1:c.754A>G

NM_001130979.1:c.847A>G

NM_001130980.1:c.847A>G

NM_001130981.1:c.847A>G

NM_001130982.1:c.850A>G

NM_001130983.1:c.757A>G

NM_001130984.1:c.757A>G

NM_001130985.1:c.850A>G

NM_001130986.1:c.757A>G

NM_001130987.1:c.850A>G

NM_003494.3:c.754A>G

NM_001130455.2:c.757A>G

NM_001130976.2:c.754A>G

NM_001130977.2:c.754A>G

NM_001130978.2:c.754A>G

NM_001130979.2:c.847A>G

NM_001130980.2:c.847A>G

NM_001130981.2:c.847A>G

NM_001130982.2:c.850A>G

NM_001130983.2:c.757A>G

NM_001130984.2:c.757A>G

NM_001130985.2:c.850A>G

NM_001130986.2:c.757A>G

NM_003494.4:c.754A>G

Likely Pathogenic

PP4 PP3 PM3_Supporting PM5 PM2_Supporting

Evidence Links 0

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 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_003494.4: c.754A>G variant in DYSF, which is also known as NM_001130987.2: c.850A>G p.(Thr284Ala), is a missense variant expected to cause the substitution of threonine for alanine at residue 252, p.(Ala252Thr). This variant has been reported in a homozygous state in one individual with limb-girdle muscular dystrophy without reported familial consanguinity (0.5 pts, ClinVar SCV001164501.1; PM3_Supporting, PP4). This variant is absent from gnomAD v.4.1.0, meeting the criteria for PM2_Supporting. The computational predictor REVEL gives a score of 0.931, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In addition, another missense variant at the same codon, NM_003494.4: c.755C>T p.(Thr252Met), has been classified as pathogenic by the ClinGen LGMD VCEP (PM5). In summary, this variant meets the criteria to be classified as Likely 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 2.0.0; 04/29/2026): PM3_Supporting, PP4, PM2_Supporting, PP3, PM5.

PP4

At least one individual with this variant displayed progressive limb girdle muscle weakness or had a clinical suspicion of LGMD (ClinVar SCV001164501.1; PP4).

PP3

The computational predictor REVEL gives a score of 0.931, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function. SpliceAI shows no splice impact.

PM3_Supporting

This variant has been reported in a homozygous state in one individual with limb-girdle muscular dystrophy without reported familial consanguinity (0.5 pts, ClinVar SCV001164501.1; PM3_Supporting).

PM5

Another missense variant at the same codon, NM_003494.4: c.755C>T p.(Thr252Met), has been classified as pathogenic by the ClinGen LGMD VCEP (PM5). PP3 applies for both curated and comparison variant SpliceAI score 0 for both variants No benign missense variation at residue and not near an intron/exon boundary.

PM2_Supporting

This variant is absent from gnomAD v.4.1.0, meeting the criteria for PM2_Supporting.

Curation History

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