rs1553522751

Variant names:

• chr2-71516996-A-T
• rs1553522751
• NM_001130987.2:c.959A>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001130987.2(DYSF):​c.959A>T​(p.Asp320Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D320D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.33
• Publications: 1 publications found

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]

DYSF Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuromuscular disease caused by qualitative or quantitative defects of dysferlin

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• autosomal recessive limb-girdle muscular dystrophy type 2B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• distal myopathy with anterior tibial onset

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy, Paradas type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Miyoshi myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain 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 2-71516996-A-T is Pathogenic according to our data. Variant chr2-71516996-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 555770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.959A>T	p.Asp320Val	missense_variant	Exon 10 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.863A>T	p.Asp288Val	missense_variant	Exon 9 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.959A>T	p.Asp320Val	missense_variant	Exon 10 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.863A>T	p.Asp288Val	missense_variant	Exon 9 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin Pathogenic:1

Oct 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 288 of the DYSF protein (p.Asp288Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of DYSF-related disease (PMID: 25591676, 27647186, 28403181, 30107846). 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: 555770). 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 not expected to disrupt DYSF protein function. For these reasons, this variant has been classified as Pathogenic. -

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

Dec 20, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Miyoshi muscular dystrophy 1 Pathogenic:1

Oct 07, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	.;.;.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.5	.;.;M;.;M;.;.;.;.;.;.
PhyloP100		6.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;D;D;D;D;D;D;D;D;D
Vest4		0.85
MutPred		0.83		.;.;Loss of catalytic residue at D288 (P = 0.0265);.;Loss of catalytic residue at D288 (P = 0.0265);.;.;.;.;.;.;
MVP		0.97
MPC		0.67
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.71
gMVP		0.75
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553522751; hg19: chr2-71744126;