rs863223283

Positions:

• chr7-94600843-CTTTGT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003919.3(SGCE):​c.835_839del​(p.Thr279AlafsTer17) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000686 in 1,458,160 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SGCE NM_003919.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.04

Genes affected

SGCE (HGNC:10808): (sarcoglycan epsilon) This gene encodes the epsilon member of the sarcoglycan family. Sarcoglycans are transmembrane proteins that are components of the dystrophin-glycoprotein complex, which link the actin cytoskeleton to the extracellular matrix. Unlike other family members which are predominantly expressed in striated muscle, the epsilon sarcoglycan is more broadly expressed. Mutations in this gene are associated with myoclonus-dystonia syndrome. This gene is imprinted, with preferential expression from the paternal allele. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. A pseudogene associated with this gene is located on chromosome 2. [provided by RefSeq, Oct 2016]

CASD1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-94600843-CTTTGT-C is Pathogenic according to our data. Variant chr7-94600843-CTTTGT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94600843-CTTTGT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCE	NM_003919.3	c.835_839del	p.Thr279AlafsTer17	frameshift_variant	7/11	ENST00000648936.2	NP_003910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCE	ENST00000648936.2	c.835_839del	p.Thr279AlafsTer17	frameshift_variant	7/11		NM_003919.3	ENSP00000497130	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458160 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 725244

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 22, 2021	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2024	Reported previously in a patient with jerky arm movements, jerky tremor of the neck, paroxysmal non-epileptic spells, proximal upper extremity myoclonus, and dystonic finger flexion; two other family members were reported to be affected but did not undergo genetic testing (PMID: 37637852); Reported previously in 8 family members with myoclonus-dystonia; however, these family members also harbored a missense in the DRD2 gene (PMID: 12402271); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10220438, 24297365, 15389977, 12821748, 18362280, 16227522, 12874409, 12391338, 33200041, 12402271, 37637852) -

Myoclonic dystonia 11 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2022	This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr279Alafs*17) in the SGCE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGCE are known to be pathogenic (PMID: 12821748, 15389977, 17853490, 24297365). This premature translational stop signal has been observed in individuals with myoclonus dystonia (PMID: 12402271, 16227522, 18362280). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 5772). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs863223283; hg19: chr7-94230155;