2-71520871-C-G

Variant names:

• chr2-71520871-C-G
• rs766891289
• NM_001130987.2:c.1116C>G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001130987.2(DYSF):​c.1116C>G​(p.Ser372Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,826 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 the same amino acid substitution has been previously reported as Likely pathogenic in Lovd.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DYSF NM_001130987.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• 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 20 ACMG points.

• PS1: Transcript NM_001130987.2 (DYSF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a domain C2 3 (size 136) in uniprot entity DYSF_HUMAN there are 42 pathogenic changes around while only 4 benign (91%) in NM_001130987.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 2-71520871-C-G is Pathogenic according to our data. Variant chr2-71520871-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 288183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71520871-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYSF	NM_001130987.2	c.1116C>G	p.Ser372Arg	missense_variant	Exon 12 of 56	ENST00000410020.8	NP_001124459.1
DYSF	NM_003494.4	c.1020C>G	p.Ser340Arg	missense_variant	Exon 11 of 55	ENST00000258104.8	NP_003485.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYSF	ENST00000410020.8	c.1116C>G	p.Ser372Arg	missense_variant	Exon 12 of 56	1	NM_001130987.2	ENSP00000386881.3
DYSF	ENST00000258104.8	c.1020C>G	p.Ser340Arg	missense_variant	Exon 11 of 55	1	NM_003494.4	ENSP00000258104.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251482 Hom.: 0 AF XY: 0.00 AC XY: 0 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461826 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727200

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

May 23, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25312915, 32153140, 19730931, 17698709, 35047756, 26404900, 33610434, 24438169, 21522182, 19556129, 33927379) -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Oct 30, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DYSF c.1020C>G (p.Ser340Arg) results in a non-conservative amino acid change located in the Ferlin domain (IPR012968) of 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 4e-06 in 251482 control chromosomes. c.1020C>G has been reported in the literature in the homozygous state in at least 1 individual affected with dysferlinopathy (example, Harris_2016). Further, a different c. with identical protein effect (c.1020C>A p.Ser340Arg) is pathogenic (PMID: 17698709, 21522182, 26404900). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results total loss of detectable DYSF protein in muscle tissue (example, Harris_2016). The following publication has been ascertained in the context of this evaluation (PMID: 27602406). ClinVar contains an entry for this variant (Variation ID: 288183). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.S340R in DYSF (NM_003494.4) has been reported previously multiple affected individuals with dysferlinopathy (Cacciottolo M et al; Magri F et al). The reported indviduals harbor a different nucleotide change c.1020C>A but the same amino acid variant. The variant has been submitted to clinvar with conflicting interpretations: VUS/Likely Pathogenic. This variant is also referred to as Ser372Arg on a different transcript. The p.S340R variant is observed in 1/1,13,756 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.S340R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The serine residue at codon 340 of DYSF is conserved in all mammalian species. The nucleotide c.1020 in DYSF is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Qualitative or quantitative defects of dysferlin Pathogenic:1

Jul 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 17698709, 21522182, 26404900, 33610434). ClinVar contains an entry for this variant (Variation ID: 288183). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;.;.;.;T;.;.;.;.;.;.
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	Benign	0.081	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.8	.;.;M;.;M;.;.;.;.;.;.
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		0.99	D
GERP RS		2.5
Varity_R		0.73
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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;