rs766891289

chr2-71520871-C-Achr2-71520871-C-Gchr2-71520871-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001130987.2(DYSF):c.1116C>A(p.Ser372Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,828 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Synonymous variant affecting the same amino acid position (i.e. S372S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.09

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 18 ACMG points.

• PS1: Transcript NM_001130987.2 (DYSF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 288183
• PM1: In a domain C2 3 (size 136) in uniprot entity DYSF_HUMAN there are 52 pathogenic changes around while only 18 benign (74%) in NM_001130987.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 2-71520871-C-A is Pathogenic according to our data. Variant chr2-71520871-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71520871-C-A is described in Lovd as [Likely_pathogenic]. Variant chr2-71520871-C-A is described in Lovd as [Likely_pathogenic]. Variant chr2-71520871-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DYSF	NM_001130987.2	c.1116C>A	p.Ser372Arg	missense_variant	12/56	ENST00000410020.8
DYSF	NM_003494.4	c.1020C>A	p.Ser340Arg	missense_variant	11/55	ENST00000258104.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DYSF	ENST00000410020.8	c.1116C>A	p.Ser372Arg	missense_variant	12/56	1	NM_001130987.2	A1
DYSF	ENST00000258104.8	c.1020C>A	p.Ser340Arg	missense_variant	11/55	1	NM_003494.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251482 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461828 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727200

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000288183,VCV000551891, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.695, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 16, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.1116C>A (p.Ser372Arg) in DYSF gene has been observed in combination with a different variant in the the DYSF gene or in the homozygous state in several individuals affected with dysferlinopathy (Nguyen K et al., 2007; Magri F et al., 2015). This variant has allele frequency 0.0007% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Ser at position 372 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ser372Arg in DYSF is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 01, 2021

- -

Miyoshi muscular dystrophy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 16, 2023

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 19, 2023

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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYSF protein function. ClinVar contains an entry for this variant (Variation ID: 551891). This missense change has been observed in individual(s) with dysferlinopathy (PMID: 17698709, 21522182, 26404900; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 340 of the DYSF protein (p.Ser340Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationTaster	Benign	0.61	D;D;D;D;D;D;N;N;N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.92	P;P;D;P;D;P;D;D;D;P;P
Vest4		0.99
MutPred		0.86		.;.;Gain of sheet (P = 0.0221);.;Gain of sheet (P = 0.0221);.;.;.;.;.;.;
MVP		0.87
MPC		0.57
ClinPred		0.98	D
GERP RS		2.5
Varity_R		0.73
gMVP		0.82

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: rs766891289; hg19: chr2-71748001;