VCV002203093.4 - ClinVar

NM_001130987.2(DYSF):c.4078C>G (p.Arg1360Gly)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001130987.2(DYSF):c.4078C>G (p.Arg1360Gly)

Variation ID: 2203093 Accession: VCV002203093.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p13.2 2: 71611483 (GRCh38) [ NCBI UCSC ] 2: 71838613 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Jun 17, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001130987.2:c.4078C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001124459.1:p.Arg1360Gly	missense
NM_003494.4:c.4024C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003485.1:p.Arg1342Gly	missense
NM_001130455.2:c.4027C>G	NP_001123927.1:p.Arg1343Gly	missense
NM_001130976.2:c.3982C>G	NP_001124448.1:p.Arg1328Gly	missense
NM_001130977.2:c.3982C>G	NP_001124449.1:p.Arg1328Gly	missense
NM_001130978.2:c.4024C>G	NP_001124450.1:p.Arg1342Gly	missense
NM_001130979.2:c.4117C>G	NP_001124451.1:p.Arg1373Gly	missense
NM_001130980.2:c.4075C>G	NP_001124452.1:p.Arg1359Gly	missense
NM_001130981.2:c.4075C>G	NP_001124453.1:p.Arg1359Gly	missense
NM_001130982.2:c.4120C>G	NP_001124454.1:p.Arg1374Gly	missense
NM_001130983.2:c.4027C>G	NP_001124455.1:p.Arg1343Gly	missense
NM_001130984.2:c.3985C>G	NP_001124456.1:p.Arg1329Gly	missense
NM_001130985.2:c.4078C>G	NP_001124457.1:p.Arg1360Gly	missense
NM_001130986.2:c.3985C>G	NP_001124458.1:p.Arg1329Gly	missense
NC_000002.12:g.71611483C>G
NC_000002.11:g.71838613C>G
NG_008694.1:g.162861C>G
LRG_845:g.162861C>G
LRG_845t1:c.4024C>G	LRG_845p1:p.Arg1342Gly
LRG_845t2:c.4078C>G	LRG_845p2:p.Arg1360Gly

... more HGVS ... less HGVS

Protein change

R1329G, R1373G, R1374G, R1342G, R1343G, R1359G, R1328G, R1360G

Other names

Canonical SPDI

NC_000002.12:71611482:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DYSF		-	-	GRCh38 GRCh37	4062	4111

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Qualitative or quantitative defects of dysferlin	Pathogenic (1)	criteria provided, single submitter	Dec 4, 2022	RCV002664240.3
Miyoshi muscular dystrophy 1	Likely pathogenic (1)	criteria provided, single submitter	Mar 14, 2024	RCV003459773.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 04, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Qualitative or quantitative defects of dysferlin Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003524595.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 21522182‚ 27647186 Comment: This variant disrupts the p.Arg1342 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21522182). This … (more) This variant disrupts the p.Arg1342 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21522182). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 expected to disrupt DYSF protein function. This missense change has been observed in individual(s) with limb girdle muscular dystrophy type 2B (PMID: 27647186). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1342 of the DYSF protein (p.Arg1342Gly). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Miyoshi muscular dystrophy 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004196501.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Comment:

This variant disrupts the p.Arg1342 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21522182). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 expected to disrupt DYSF protein function. This missense change has been observed in individual(s) with limb girdle muscular dystrophy type 2B (PMID: 27647186). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1342 of the DYSF protein (p.Arg1342Gly). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Dysferlin Gene Mutation Spectrum in a Large Cohort of Chinese Patients with Dysferlinopathy.	Jin SQ	Chinese medical journal	2016	PMID: 27647186
Muscular dystrophy with marked Dysferlin deficiency is consistently caused by primary dysferlin gene mutations.	Cacciottolo M	European journal of human genetics : EJHG	2011	PMID: 21522182

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001130987.2(DYSF):c.4078C>G (p.Arg1360Gly)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...