NM_000337.6:c.493C>T
Variant summary
Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PVS1PP4_StrongPM3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000337.6: c.493C>T p.(Arg165Ter) variant in SGCD is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/9, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least three patients with limb girdle muscular dystrophy, including in homozygous state in at least two patients from two families (1.0 pt, PMID:19770540, 10735275) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent delta-sarcoglycan protein expression in skeletal muscle by IHC, which is highly specific for SGCD-related LGMD (PP4_Strong; PMID:19770540). The highest population minor allele frequency for this variant is 0.00004827 (2/41432 genome chromosomes) in the African/African American population of gnomAD v3.1.2, which is lower than the ClinGen LGMD VCEP threshold for PM2_Supporting (<0.00009), meeting this criterion (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; 01/08/2025): PVS1, PP4_Strong, PM3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340747/MONDO:0015152/186
Frequency
Consequence
NM_000337.6 stop_gained
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive limb-girdle muscular dystrophyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- autosomal recessive limb-girdle muscular dystrophy type 2FInheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, Ambry Genetics
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- dilated cardiomyopathy 1LInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 15 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SGCD | ENST00000337851.9 | c.493C>T | p.Arg165* | stop_gained | Exon 6 of 9 | 1 | NM_000337.6 | ENSP00000338343.4 | ||
SGCD | ENST00000435422.7 | c.490C>T | p.Arg164* | stop_gained | Exon 5 of 8 | 1 | ENSP00000403003.2 | |||
SGCD | ENST00000517913.5 | c.493C>T | p.Arg165* | stop_gained | Exon 8 of 10 | 5 | ENSP00000429378.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000815 AC: 2AN: 245526 AF XY: 0.0000150 show subpopulations
GnomAD4 exome AF: 0.00000617 AC: 9AN: 1458790Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 6AN XY: 725522 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74450 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2F Pathogenic:3
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This sequence change creates a premature translational stop signal (p.Arg165*) in the SGCD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGCD are known to be pathogenic (PMID: 8841194, 10735275, 10838250). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with limb-girdle muscular dystrophy (PMID: 10735275, 19770540). ClinVar contains an entry for this variant (Variation ID: 8172). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
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Nonsense 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: 25525159, 19770540, 35416532, 33250842, 10735275) -
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
The NM_000337.6: c.493C>T p.(Arg165Ter) variant in SGCD is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 6/9, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least three patients with limb girdle muscular dystrophy, including in homozygous state in at least two patients from two families (1.0 pt, PMID: 19770540, 10735275) (PM3). At least one patient with this variant displayed progressive limb girdle muscle weakness as well as absent delta-sarcoglycan protein expression in skeletal muscle by IHC, which is highly specific for SGCD-related LGMD (PP4_Strong; PMID: 19770540). The highest population minor allele frequency for this variant is 0.00004827 (2/41432 genome chromosomes) in the African/African American population of gnomAD v3.1.2, which is lower than the ClinGen LGMD VCEP threshold for PM2_Supporting (<0.00009), meeting this criterion (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; 01/08/2025): PVS1, PP4_Strong, PM3, PM2_Supporting. -
Autosomal recessive limb-girdle muscular dystrophy type 2F;C1847667:Dilated cardiomyopathy 1L Pathogenic:1
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. -
Dilated cardiomyopathy 1L Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at