rs201049092

Positions:

• chr2-71553110-G-A
• chr2-71553110-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2_Supporting PS3_Moderate PP4_Strong PM3_Strong PP1 PP3

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA241938/MONDO:0015152/180

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7 U:2
• Conservation: PhyloP100: 10.0

Genes affected

DYSF (HGNC:3097): (dysferlin) The protein encoded by this gene belongs to the ferlin family and is a skeletal muscle protein found associated with the sarcolemma. It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. In addition, the protein encoded by this gene binds caveolin-3, a skeletal muscle membrane protein which is important in the formation of caveolae. Specific mutations in this gene have been shown to cause autosomal recessive limb girdle muscular dystrophy type 2B (LGMD2B) as well as Miyoshi myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.1906G>A	p.Gly636Arg	missense_variant	20/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.1852G>A	p.Gly618Arg	missense_variant	20/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.1906G>A	p.Gly636Arg	missense_variant	20/56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.1852G>A	p.Gly618Arg	missense_variant	20/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251442 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461840 Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 12, 2023	Variant summary: DYSF c.1852G>A (p.Gly618Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251442 control chromosomes (gnomAD). c.1852G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Limb-Girdle Muscular Dystrophy or Miyoshi Myopathy with confirmed absense of DYSF protein (e.g. Kawabe_2004, Krahn_2009, Nishikawa_2016, Charnay_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33927379, 15469449, 18853459, 26088049). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen	Jan 08, 2025	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. -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 13, 2014	- -

Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 29, 2018	- -
Uncertain significance, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Gly636Arg variant in DYSF was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Gly636Arg variant in DYSF has been reported in 6 individuals with LGMD (PMID: 26404900, 17828519, 18853459, 15469449, 26088049), and has been identified in 0.004484% (1/22300) of Finnish chromosomes and 0.004484% (1/22300) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201049092). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, the clinical significance of the p.Gly636Arg variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015). -

Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 15, 2024

- -

Miyoshi muscular dystrophy 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 09, 2023

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYSF protein function. ClinVar contains an entry for this variant (Variation ID: 195490). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 15469449, 18853459, 26088049, 26404900). This variant is present in population databases (rs201049092, gnomAD 0.004%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 618 of the DYSF protein (p.Gly618Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	.;.;.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	.;.;H;.;H;.;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.2	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;D
Vest4		0.99
MutPred		0.90		.;.;Loss of ubiquitination at K623 (P = 0.0516);.;Loss of ubiquitination at K623 (P = 0.0516);.;.;.;.;.;.;
MVP		0.98
MPC		0.70
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.82
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201049092; hg19: chr2-71780240; COSMIC: COSV50287268;