5-156595042-C-T

Variant names:

• chr5-156595042-C-T
• rs121909295
• NM_000337.6:c.493C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PVS1 PP4_Strong PM3 PM2_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:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SGCD NM_000337.6 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: -0.0590
• Publications: 6 publications found

Genes affected

SGCD (HGNC:10807): (sarcoglycan delta) The protein encoded by this gene is one of the four known components of the sarcoglycan complex, which is a subcomplex of the dystrophin-glycoprotein complex (DGC). DGC forms a link between the F-actin cytoskeleton and the extracellular matrix. This protein is expressed most abundantly in skeletal and cardiac muscle. Mutations in this gene have been associated with autosomal recessive limb-girdle muscular dystrophy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding distinct isoforms have been observed for this gene. [provided by RefSeq, Jul 2008]

SGCD Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2F

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• dilated cardiomyopathy 1L

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000337.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCD	NM_000337.6	MANE Select	c.493C>T	p.Arg165*	stop_gained	Exon 6 of 9	NP_000328.2
	SGCD	NM_001128209.2		c.490C>T	p.Arg164*	stop_gained	Exon 5 of 8	NP_001121681.1	Q92629-1
	SGCD	NM_172244.3		c.493C>T	p.Arg165*	stop_gained	Exon 6 of 8	NP_758447.1	Q92629-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCD	ENST00000337851.9	TSL:1 MANE Select	c.493C>T	p.Arg165*	stop_gained	Exon 6 of 9	ENSP00000338343.4	Q92629-2
	SGCD	ENST00000435422.7	TSL:1	c.490C>T	p.Arg164*	stop_gained	Exon 5 of 8	ENSP00000403003.2	Q92629-1
	SGCD	ENST00000959784.1		c.544C>T	p.Arg182*	stop_gained	Exon 7 of 10	ENSP00000629843.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000815 AC: 2 AN: 245526 AF XY: 0.0000150

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 FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458790 Hom.: 0 Cov.: 30 AF XY: 0.00000827 AC XY: 6 AN XY: 725522

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85760

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1110250

Other (OTH) AF: 0.00 AC: 0 AN: 60248

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74450

African (AFR) AF: 0.0000481 AC: 2 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2F (3)
2	-	-	not provided (2)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy (1)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2F;C1847667:Dilated cardiomyopathy 1L (1)
1	-	-	Dilated cardiomyopathy 1L (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	35
DANN	Benign	0.96
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.49	N
PhyloP100		-0.059
Vest4		0.94
GERP RS		-5.9
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121909295; hg19: chr5-156022052; COSMIC: COSV106104817;