rs149827237

chr2-71515716-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_001130987.2(DYSF):c.853C>T(p.Arg285Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,614,088 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R285Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 1.32

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_001130987.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• PP5: Variant 2-71515716-C-T is Pathogenic according to our data. Variant chr2-71515716-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 284800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71515716-C-T is described in Lovd as [Likely_pathogenic]. Variant chr2-71515716-C-T is described in Lovd as [Pathogenic]. Variant chr2-71515716-C-T is described in Lovd as [Pathogenic]. Variant chr2-71515716-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.853C>T	p.Arg285Trp	missense_variant	8/56	ENST00000410020.8
DYSF	NM_003494.4	c.757C>T	p.Arg253Trp	missense_variant	7/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.853C>T	p.Arg285Trp	missense_variant	8/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.757C>T	p.Arg253Trp	missense_variant	7/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152102 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000123 AC: 31 AN: 251448 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000170 AC: 249 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.000166 AC XY: 121 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000197

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74422

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.0000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2023	Observed in the homozygous state in one individual with isolated elevated creatine kinase levels who had only a mild reduction of dysferlin on western blot analysis (Nguyen et al., 2005); 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: 27666772, 23891399, 18853459, 25868377, 16010686, 28888072, 27017278, 33215690, 31589614, 33715265, 33610434, 36672942, 30919934) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 03, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 18, 2020	PS4_moderate, PM2, PM3 -

Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jun 16, 2020	This DYSF variant (rs149827237) is rare (<0.1%) in a large population dataset (gnomAD: 32/282838 total alleles; 0.011%; no homozygotes) and has an entry in ClinVar. This variant has been reported previously in combination with another DYSF variant in individuals affected with LGMDR2 and in a homozygous state in an individual with isolated hyperCKemia. Three bioinformatic tools queried predict that p.Arg285Trp would be damaging, and the arginine residue at this position is strongly conserved across the species assessed. This variant is not predicted to affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. We consider this variant to be likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 18, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 01, 2021	- -

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

Sep 24, 2021

- -

Miyoshi muscular dystrophy 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 23, 2023

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 253 of the DYSF protein (p.Arg253Trp). This variant is present in population databases (rs149827237, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of dysferlinopathies (PMID: 16010686, 18853459, 25868377, 27666772, 30919934; Invitae). 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: 284800). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	24
Dann	Pathogenic	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.8	D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.61
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		0.85
MVP		0.89
MPC		0.65
ClinPred		0.71	D
GERP RS		4.0
Varity_R		0.89
gMVP		0.65

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: rs149827237; hg19: chr2-71742846; COSMIC: COSV50284000;