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 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.1906G>A (p.Gly636Arg)

CA241938

195490 (ClinVar)

Gene: DYSF
Condition: autosomal recessive limb-girdle muscular dystrophy
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 511ac915-d19b-4978-9694-66edab214cc8
Approved on: 2025-01-08
Published on: 2025-01-08

HGVS expressions

NM_001130987.2:c.1906G>A
NM_001130987.2(DYSF):c.1906G>A (p.Gly636Arg)
NC_000002.12:g.71553110G>A
CM000664.2:g.71553110G>A
NC_000002.11:g.71780240G>A
CM000664.1:g.71780240G>A
NC_000002.10:g.71633748G>A
NG_008694.1:g.104488G>A
ENST00000258104.8:c.1852G>A
ENST00000410020.8:c.1906G>A
ENST00000258104.7:c.1852G>A
ENST00000394120.6:c.1855G>A
ENST00000409366.5:c.1855G>A
ENST00000409582.7:c.1903G>A
ENST00000409651.5:c.1948G>A
ENST00000409744.5:c.1813G>A
ENST00000409762.5:c.1903G>A
ENST00000410020.7:c.1906G>A
ENST00000410041.1:c.1906G>A
ENST00000413539.6:c.1945G>A
ENST00000429174.6:c.1852G>A
NM_001130455.1:c.1855G>A
NM_001130976.1:c.1810G>A
NM_001130977.1:c.1810G>A
NM_001130978.1:c.1852G>A
NM_001130979.1:c.1945G>A
NM_001130980.1:c.1903G>A
NM_001130981.1:c.1903G>A
NM_001130982.1:c.1948G>A
NM_001130983.1:c.1855G>A
NM_001130984.1:c.1813G>A
NM_001130985.1:c.1906G>A
NM_001130986.1:c.1813G>A
NM_001130987.1:c.1906G>A
NM_003494.3:c.1852G>A
NM_001130455.2:c.1855G>A
NM_001130976.2:c.1810G>A
NM_001130977.2:c.1810G>A
NM_001130978.2:c.1852G>A
NM_001130979.2:c.1945G>A
NM_001130980.2:c.1903G>A
NM_001130981.2:c.1903G>A
NM_001130982.2:c.1948G>A
NM_001130983.2:c.1855G>A
NM_001130984.2:c.1813G>A
NM_001130985.2:c.1906G>A
NM_001130986.2:c.1813G>A
NM_003494.4:c.1852G>A
More

Pathogenic

Met criteria codes 6
PP4_Strong PS3_Moderate PM3_Strong PM2_Supporting PP3 PP1
Not Met criteria codes 20
PM6 PM1 PM5 PM4 PVS1 BA1 BS3 BS1 BS4 BS2 BP5 BP7 BP3 BP2 BP4 BP1 PS2 PS4 PS1 PP2

Evidence Links 1

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.1852G>A variant in DYSF, which is also known as NM_001130987.2: c.1906G>A 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 at least 7 unrelated individuals with LGMD2B. Of those individuals, at least 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.2811-2A>C, 1.0 pt, PMID: 36983702). In addition, three unrelated individuals were homozygous for the variant (1.0 pt, PMID: 26088049, 18853459, 32400077) (PM3_Strong). At least one patient with this variant displayed progressive weakness and reduced dysferlin protein expression, which is highly specific for DYSF-related LGMD (PP4_Strong, PMID: 36983702). The variant was also reported to co-segregate with the disease in one affected family member (PP1; PMID: 12471055). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 (1/21646 alleles) in the European (Finnish) population, which is less than the ClinGen LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (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 0.93, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). Another nucleotide change resulting in the same amino acid change, c.1852G>C p.(Gly618Arg), has been reported in association with LGMD (PMID: 30564623) and classified as pathogenic by the LGMD VCEP. 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): PP4_Strong, PM3_Strong, PM2_Supporting, PP3, PP1, PS3_Moderate.
Met criteria codes
PP4_Strong
At least one patient with this variant displayed progressive weakness and significantly reduced dysferlin protein expression, which is highly specific for DYSF-related LGMD (PP4_Strong, PMID: 36983702).
PS3_Moderate
Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).
Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). PubMed:35028538
PM3_Strong
This variant has been detected in at least 7 unrelated individuals with LGMD2B. Of those individuals, at least 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (c.2811-2A>C, 1.0 pt, PMID: 36983702). Three unrelated individuals were homozygous for the variant (1.0 pt, PMID: 26088049, 18853459, 32400077) (PM3_Strong).
PM2_Supporting
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00004 (1/21646 alleles) in European (Finnish) population, which is less than to the ClinGen LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting).
PP3
The computational predictor REVEL gives a score of 0.93, which exceeds the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3).
PP1
The variant was also reported to co-segregate with the disease in one affected family member (PP1; PMID: 12471055).
Not Met criteria codes
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
Another nucleotide change resulting in the same amino acid change, c.1852G>C p.(Gly618Arg), has been reported in association with LGMD (PMID: 30564623) and was classified as pathogenic by the LGMD VCEP. Applied PS1 to c.1852G>C and so opted not to apply here.
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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