2-71553110-G-C

Position:

• chr2-71553110-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2_Supporting PP4_Strong PS1 PS3 PP3

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA277611/MONDO:0015152/180

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• 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 14 ACMG points.

• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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>C	p.Gly636Arg	missense_variant	20/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.1852G>C	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>C	p.Gly636Arg	missense_variant	20/56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.1852G>C	p.Gly618Arg	missense_variant	20/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

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>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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 02, 2016

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 28, 2015

- -

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	Uncertain	25
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;