rs1553556116

Variant names:

• chr2-71570685-C-T
• rs1553556116
• NM_001130987.2:c.3172C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001130987.2(DYSF):​c.3172C>T​(p.Arg1058Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.47

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 2-71570685-C-T is Pathogenic according to our data. Variant chr2-71570685-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 498954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71570685-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-71570685-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.3172C>T	p.Arg1058Trp	missense_variant	Exon 29 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.3118C>T	p.Arg1040Trp	missense_variant	Exon 29 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.3172C>T	p.Arg1058Trp	missense_variant	Exon 29 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.3118C>T	p.Arg1040Trp	missense_variant	Exon 29 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461712 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727178

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 10, 2016

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 10, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jun 01, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DYSF c.3118C>T (p.Arg1040Trp) results in a non-conservative amino acid change located in the Peroxin/Ferlin domain (IPR006614) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250590 control chromosomes. c.3118C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Walter_2013, Izumi_2015, Harris_2016, ten Dam_2019, Morales_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The identified missense variant (c.3172C>T; p.Arg1058Trp) in DYSF gene has been previously reported as (p.Arg1040Trp) in the ClinVar databse. The variant has been previously reported in individuals affected with dysferlinopathy (Izumi R, 2020) and has been reported as Likely Pathogenic by the ClinVar database. In at least one individual affected with dysferlinopathy, the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine with tryptophan at 1058 codon of the DYSF protein. There is a moderate physicochemical difference between arginine and tryptophan. The amino acid change p.Arg1058Trp in DYSF is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted to be damaging by both SIFT and PolyPhen2. The p.Arg1058Trp variant is novel (not in any individuals) in gnomAD database. For these reasons, this variant has been classified as Likely Pathogenic. -

Miyoshi muscular dystrophy 1 Pathogenic:1

Mar 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1040 of the DYSF protein (p.Arg1040Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 23406536, 27066573, 30919934). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 498954). 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 95%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;.;M;.;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.2	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	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		0.81
MutPred		0.61		.;.;Loss of disorder (P = 0.0024);.;Loss of disorder (P = 0.0024);.;.;.;.;.;.;
MVP		0.98
MPC		0.66
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.85

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: rs1553556116; hg19: chr2-71797815;