Evidence Repository - Clinical Genome Resources

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Variant: NM_001130987.2(DYSF):c.1906G>C (p.Gly636Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA277611

217224 (ClinVar)

Gene: DYSF

Condition: autosomal recessive limb-girdle muscular dystrophy

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 246e953e-933a-43da-a7cf-a1931fc84263

Approved on: 2025-01-08

Published on: 2025-01-08

HGVS expressions

NM_001130987.2:c.1906G>C

NM_001130987.2(DYSF):c.1906G>C (p.Gly636Arg)

NC_000002.12:g.71553110G>C

CM000664.2:g.71553110G>C

NC_000002.11:g.71780240G>C

CM000664.1:g.71780240G>C

NC_000002.10:g.71633748G>C

NG_008694.1:g.104488G>C

ENST00000258104.8:c.1852G>C

ENST00000410020.8:c.1906G>C

ENST00000258104.7:c.1852G>C

ENST00000394120.6:c.1855G>C

ENST00000409366.5:c.1855G>C

ENST00000409582.7:c.1903G>C

ENST00000409651.5:c.1948G>C

ENST00000409744.5:c.1813G>C

ENST00000409762.5:c.1903G>C

ENST00000410020.7:c.1906G>C

ENST00000410041.1:c.1906G>C

ENST00000413539.6:c.1945G>C

ENST00000429174.6:c.1852G>C

NM_001130455.1:c.1855G>C

NM_001130976.1:c.1810G>C

NM_001130977.1:c.1810G>C

NM_001130978.1:c.1852G>C

NM_001130979.1:c.1945G>C

NM_001130980.1:c.1903G>C

NM_001130981.1:c.1903G>C

NM_001130982.1:c.1948G>C

NM_001130983.1:c.1855G>C

NM_001130984.1:c.1813G>C

NM_001130985.1:c.1906G>C

NM_001130986.1:c.1813G>C

NM_001130987.1:c.1906G>C

NM_003494.3:c.1852G>C

NM_001130455.2:c.1855G>C

NM_001130976.2:c.1810G>C

NM_001130977.2:c.1810G>C

NM_001130978.2:c.1852G>C

NM_001130979.2:c.1945G>C

NM_001130980.2:c.1903G>C

NM_001130981.2:c.1903G>C

NM_001130982.2:c.1948G>C

NM_001130983.2:c.1855G>C

NM_001130984.2:c.1813G>C

NM_001130985.2:c.1906G>C

NM_001130986.2:c.1813G>C

NM_003494.4:c.1852G>C

Pathogenic

PM2_Supporting PP3 PS3 PS1 PP4_Strong

PP2 PP1 PM6 PM1 PM5 PM4 PM3 BS2 BS3 BS1 BS4 BP3 BP2 BP4 BP1 BP5 BP7 PS2 PS4 BA1 PVS1

Evidence Links 1

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Limb Girdle Muscular Dystrophy VCEP

The NM_003494.4: c.1852G>C variant in DYSF, which is also known as NM_001130987.2: c.1906G>C p.(Gly636Arg), is a missense variant predicted to cause substitution of glycine by arginine at amino acid 618 (p.Gly618Arg). This variant has been detected in one individual with a clinical diagnosis or suspicion of LGMD and absent dysferlin protein expression (PP4_Strong), in whom it was identified in unknown phase with a variant classified as at least likely pathogenic (c.5836_5839del p.(Gln1946Trpfs*19), 0.25 pts, PMID: 30564623, Jain Foundation Dysferlin Registry internal data communication) (PM3_Supporting not met). This variant is absent from gnomAD v2.1.1 and 3.1.2 (PM2_Supporting). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly636Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). The computational predictor REVEL gives a score of 0.928, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3). The same amino acid change, p.(Gly618Arg), resulting from a different nucleotide change, c.1852G>A (NM_003494.4), is classified as pathogenic for autosomal recessive LGMD by the ClinGen LGMD VCEP (PS1). 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): PM2_Supporting, PP4_Strong, PS1, PS3_Moderate, PP3.

PM2_Supporting

This variant is absent from gnomAD v2.1.1 and 3.1.2 (PM2_Supporting).

PP3

The computational predictor REVEL gives a score of 0.928, which is above the LGMD VCEP threshold of 0.70, evidence that correlates with impact to DYSF function (PP3).

PS3

Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly636Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).

PS1

The same amino acid change, p.(Gly618Arg), resulting from a different nucleotide change, c.1852G>A (NM_003494.4), is classified as pathogenic for LGMD by the ClinGen LGMD VCEP (PS1).

PP4_Strong

Identified in trans with an LP variant in an individual with clinically diagnosed LGMD.

PP2