2-71661900-G-T

Variant names:

• chr2-71661900-G-T
• rs886042110
• NM_001130987.2:c.5003+1249G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP1 PM2_Supporting PM3_Strong PVS1_Moderate PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.4886+1249G>T variant in DYSF, which is also known as NM_001130987.2: c.5003+1249G>T, is a deep intronic variant. SpliceAI gives a score of 0.26 for donor gain and 0.12 for acceptor gain. RNAseq analysis has demonstrated two splice effects of this variant: activation of a cryptic splice site within DYSF intron 44 that leads to the insertion of 177 bp intronic sequence and a non-frameshifting insertion of 59 amino acids, p.Lys1646_Met1647ins59; and activation of a cryptic splice site within DYSF intron 44 that leads to the insertion of 88 bp of intronic sequence and a frameshift with nonsense mediated decay expected, p.Lys1646AsnfsTer13 (PMID:36983702; PVS1_Moderate_RNA). This variant has been reported in at least four individuals with features consistent with LGMD (PMID:26273692, 36983702, 30564623, 25493284), including confirmed in trans with a likely pathogenic or pathogenic variant in one patient (NM_003494.4: c.1168G>A p.(Asp390Asn), 1.0 pt, PMID:26273692) and in unknown phase with a pathogenic variant in two patients (NM_003494.4: c.857T>A p.(Val286Glu), 0.5 pts, PMID:36983702, 30564623, 25493284; NM_003494.4: c.1834C>T p.(Gln612Ter), 0.5 pts, PMID:25493284) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in DYSF showed progressive muscle weakness and absent dysferlin protein expression in skeletal muscle and/or blood monocytes, which is highly specific for DYSF-related LGMD (PMID:36983702, 25493284; PP4_Strong). In addition, this variant has been shown to co-segregate with the LGMD phenotype in one affected family member (PMID:30564623, 30564623) (PP1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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; 04/23/2025): PVS1_Moderate_RNA, PM3_Strong, PP4_Strong, PP1, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10603819/MONDO:0015152/180

• Frequency: Genomes: not found (cov: 32)
• Consequence: DYSF NM_001130987.2 intron
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 0.168
• Publications: 8 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 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.5003+1249G>T		intron_variant	Intron 45 of 55	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4886+1249G>T		intron_variant	Intron 44 of 54	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.5003+1249G>T		intron_variant	Intron 45 of 55	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.4886+1249G>T		intron_variant	Intron 44 of 54	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Apr 23, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_003494.4: c.4886+1249G>T variant in DYSF, which is also known as NM_001130987.2: c.5003+1249G>T, is a deep intronic variant. SpliceAI gives a score of 0.26 for donor gain and 0.12 for acceptor gain. RNAseq analysis has demonstrated two splice effects of this variant: activation of a cryptic splice site within DYSF intron 44 that leads to the insertion of 177 bp intronic sequence and a non-frameshifting insertion of 59 amino acids, p.Lys1646_Met1647ins59; and activation of a cryptic splice site within DYSF intron 44 that leads to the insertion of 88 bp of intronic sequence and a frameshift with nonsense mediated decay expected, p.Lys1646AsnfsTer13 (PMID: 36983702; PVS1_Moderate_RNA). This variant has been reported in at least four individuals with features consistent with LGMD (PMID: 26273692, 36983702, 30564623, 25493284), including confirmed in trans with a likely pathogenic or pathogenic variant in one patient (NM_003494.4: c.1168G>A p.(Asp390Asn), 1.0 pt, PMID: 26273692) and in unknown phase with a pathogenic variant in two patients (NM_003494.4: c.857T>A p.(Val286Glu), 0.5 pts, PMID: 36983702, 30564623, 25493284; NM_003494.4: c.1834C>T p.(Gln612Ter), 0.5 pts, PMID: 25493284) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in DYSF showed progressive muscle weakness and absent dysferlin protein expression in skeletal muscle and/or blood monocytes, which is highly specific for DYSF-related LGMD (PMID: 36983702, 25493284; PP4_Strong). In addition, this variant has been shown to co-segregate with the LGMD phenotype in one affected family member (PMID: 30564623, 30564623) (PP1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). 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; 04/23/2025): PVS1_Moderate_RNA, PM3_Strong, PP4_Strong, PP1, PM2_Supporting.

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

Mar 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Jul 11, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 04, 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.

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

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 44 of the DYSF gene. It does not directly change the encoded amino acid sequence of the DYSF protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 59 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of DYSF-related disease (PMID: 25493284, 26273692). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 281197). Studies have shown that this variant results in the activation of a cryptic splice site in intron 44 (PMID: 25493284). For these reasons, this variant has been classified as Pathogenic.

Miyoshi muscular dystrophy 1 Pathogenic:1

Apr 19, 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
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		0.17
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.26		Position offset: -2

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

Other links and lift over

dbSNP: rs886042110; hg19: chr2-71889030;