rs757917335

Positions:

• chr2-71611481-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4_Strong PM3 PS3 PP3 PP1

This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.4022T>C variant in DYSF, which is also known as NM_001130987.2: c.4076T>C p.(Leu1359Pro), is a missense variant predicted to cause substitution of leucine by proline at amino acid 1341 (p.Leu1341Pro). This variant has been detected in a homozygous state in at least seven individuals with clinical signs of limb girdle muscular dystrophy (1.0 pt, PMID:16705711, 19528035, 22057634, 26436962, 27647186, 28403181, 34559919, 34624274) (PM3). It has also been observed in trans with a nonsense variant, c.4228C>T p.(Gln1410Ter), in one affected individual (PMID:34624274). At least one patient with this variant displayed progressive limb girdle muscle weakness and absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID:16705711, 21522182). The variant was also reported to co-segregate with the disease in six affected family members from three families (PMID:16705711, 21522182, 34624274) (PP1, capped with PP4_Strong). The filtering allele frequency of the variants is 0.0003434 for South Asian exome alleles in gnomAD v2.1.1 (the upper threshold of the 95% CI of 5/30616), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID:30292141) (PS3). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID:35028538). The computational predictor REVEL gives a score of 0.89, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). 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; 01/08/2025): PM3, PP4_Strong, PP1, PS3, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA1706888/MONDO:0015152/180

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 8.02

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS3: 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.
• PP3: 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/exons	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.4076T>C	p.Leu1359Pro	missense_variant	38/56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.4022T>C	p.Leu1341Pro	missense_variant	38/55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.4076T>C	p.Leu1359Pro	missense_variant	38/56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.4022T>C	p.Leu1341Pro	missense_variant	38/55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251292 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135886

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: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461834 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 727222

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: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 04, 2018	- -
Pathogenic, criteria provided, single submitter	research	James R Lupski Laboratory, Baylor College Of Medicine	Jul 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Apr 02, 2024	This variant is predicted to be damaging by in-silico missense prediction tools (REVEL, SIFT and Polyphen2). It was previously reported in patients affected with dysferlinopathies/ limb girdle muscular dystrophy and segregated with disease in a family [PMID: 16705711, 19528035, 22057634, 26436962, 27647186]. This variant has been reported to affect proper folding of the dysferlin C2E domain and it leads to aggregated formation of non-functional protein. [PMID: 23185377, 30292141]. -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 30, 2024

Variant summary: DYSF c.4022T>C (p.Leu1341Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251292 control chromosomes (gnomAD). c.4022T>C has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (e.g. Wenzel_2006, Ababneh_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16705711, 34624274). ClinVar contains an entry for this variant (Variation ID: 555968). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2021

- -

Miyoshi muscular dystrophy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 12, 2024

- -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1341 of the DYSF protein (p.Leu1341Pro). This variant is present in population databases (rs757917335, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive dysferlinopathies (PMID: 16705711, 19528035, 22057634, 26436962, 27647186). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 555968). 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. Experimental studies have shown that this missense change affects DYSF function (PMID: 23185377, 30292141). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;.;.;.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.1	.;.;M;.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.89
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		1.0	D;D;D;D;D;D;D;D;D;D;D
Vest4		0.84
MutPred		0.91		.;.;Loss of catalytic residue at L1341 (P = 0.0057);.;Loss of catalytic residue at L1341 (P = 0.0057);.;.;.;.;.;.;
MVP		0.94
MPC		0.82
ClinPred		0.88	D
GERP RS		4.7
Varity_R		0.90
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs757917335; hg19: chr2-71838611;