chr2-71551631-C-T

Position:

• chr2-71551631-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS3_Moderate PP4_Strong PM3_Strong PP3 PP1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.1663C>T variant in DYSF, which is also known as NM_001130987.2: c.1717C>T p.(Arg573Trp), is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 555 (p.Arg555Trp). This variant has been detected in at least nine unrelated individuals with limb girdle muscular dystrophy (PMID:16010686, 17698709, 18853459, 25591676, 25143362, 19015158), including in a homozygous state in two patients (0.75 pts, PMID:25143362,16010686) and in trans with a pathogenic variant in at least two patients (c.3708delA p.(Asp1237ThrfsTer24), 1.0 pt, PMID:19015158; c.3220_3221delCT p.(Leu1074PheTer39), 1.0 pt, PMID:25591676) (PM3_Strong). At least one patient with this variant displayed progressive limb-girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID:16010686, 25143362, 19015158, 18853459). The variant has also been reported to segregate with LGMD in two affected family members from one family (PP1; PMID:25143362). The filtering allele frequency of the variant is 0.0002685 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 3/28874), which is greater than the LGMD VCEP threshold (<0.0001) (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg555Trp 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 0.94, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). 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): PM3_Strong, PP4_Strong, PP1, PS3_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA222133/MONDO:0015152/180

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 0.553

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 12 ACMG points.

• PS3: 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.1717C>T	p.Arg573Trp	missense_variant	19/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.1663C>T	p.Arg555Trp	missense_variant	19/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.1717C>T	p.Arg573Trp	missense_variant	19/56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.1663C>T	p.Arg555Trp	missense_variant	19/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000292 AC: 7 AN: 240060 Hom.: 0 AF XY: 0.0000310 AC XY: 4 AN XY: 129144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000595

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000364 AC: 53 AN: 1456506 Hom.: 0 Cov.: 31 AF XY: 0.0000304 AC XY: 22 AN XY: 723760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000454

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000473

Gnomad4 FIN exome AF: 0.0000382

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000905 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000332 AC: 4

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2024	Published functional studies suggest a damaging effect on protein expression and localization (PMID: 35028538); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25312915, 25591676, 19493611, 16010686, 22318734, 24488599, 19015158, 26579332, 23527661, 21522182, 34559919, 33927379, 27066573, 17698709, 36983702, 32400077, 33258288, 23519732, 25143362, 25591678, 31873062, 33610434, 18853459, 32664072, 32528171, 33715265, 31066050, 36672942, 22174839, 35028538) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 18, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 08, 2022	- -

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

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 17, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 27, 2020	- -

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.1663C>T variant in DYSF, which is also known as NM_001130987.2: c.1717C>T p.(Arg573Trp), is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 555 (p.Arg555Trp). This variant has been detected in at least nine unrelated individuals with limb girdle muscular dystrophy (PMID: 16010686, 17698709, 18853459, 25591676, 25143362, 19015158), including in a homozygous state in two patients (0.75 pts, PMID: 25143362,16010686) and in trans with a pathogenic variant in at least two patients (c.3708delA p.(Asp1237ThrfsTer24), 1.0 pt, PMID: 19015158; c.3220_3221delCT p.(Leu1074PheTer39), 1.0 pt, PMID: 25591676) (PM3_Strong). At least one patient with this variant displayed progressive limb-girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 16010686, 25143362, 19015158, 18853459). The variant has also been reported to segregate with LGMD in two affected family members from one family (PP1; PMID: 25143362). The filtering allele frequency of the variant is 0.0002685 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 3/28874), which is greater than the LGMD VCEP threshold (<0.0001) (PM2_Supporting not met). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg555Trp 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 0.94, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). 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): PM3_Strong, PP4_Strong, PP1, PS3_Moderate, PP3. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 20, 2024

- -

DYSF-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

The c.1663C>T (p.Arg555Trp) variant has been reported in at least six studies in a total of 10 patients with DYSF-related disorders, including three in a homozygous state and seven in a compound heterozygous state. The p.Arg555Trp variant was absent from 90 controls but is reported at a frequency of 0.00004 in the Total population of the Exome Aggregation Consortium. Functional studies using a myoblast cell line derived from a patient carrying the p.Arg555Trp variant and a second DYSF variant showed that the variant protein was degraded by proteasomes. Treatment with protease inhibitors rescued dysferlin expression and function. Based on the evidence, the p.Arg555Trp variant is classified as pathogenic for DYSF-related disorders. -

Miyoshi muscular dystrophy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 11, 2024

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 01, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 555 of the DYSF protein (p.Arg555Trp). This variant is present in population databases (rs377735262, gnomAD 0.01%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 17698709, 25591676, 27066573). ClinVar contains an entry for this variant (Variation ID: 94278). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DYSF function (PMID: 22174839). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.25	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	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.2	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	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
MVP		0.98
MPC		0.66
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.69
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs377735262; hg19: chr2-71778761; COSMIC: COSV99251252;