rs763986788

chr17-50168470-T-TG

Variant summary

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

The NM_000023.4(SGCA):c.488dup(p.Leu164ThrfsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000629 in 1,431,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L161L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000063 (0 hom.)
• Consequence: SGCA NM_000023.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.72

Genes affected

SGCA (HGNC:10805): (sarcoglycan alpha) This gene encodes a component of the dystrophin-glycoprotein complex (DGC), which is critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. Its expression is thought to be restricted to striated muscle. Mutations in this gene result in type 2D autosomal recessive limb-girdle muscular dystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

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 17-50168470-T-TG is Pathogenic according to our data. Variant chr17-50168470-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCA	NM_000023.4	c.488dup	p.Leu164ThrfsTer27	frameshift_variant	5/10	ENST00000262018.8
SGCA	NM_001135697.3	c.488dup	p.Leu164ThrfsTer27	frameshift_variant	5/8
SGCA	NR_135553.2	n.524dup		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCA	ENST00000262018.8	c.488dup	p.Leu164ThrfsTer27	frameshift_variant	5/10	1	NM_000023.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000629 AC: 9 AN: 1431788 Hom.: 0 Cov.: 33 AF XY: 0.00000705 AC XY: 5 AN XY: 709184

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: 0.00000821

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Pathogenic:5

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 03, 2023	This premature translational stop signal has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 18996010). 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 sequence change creates a premature translational stop signal (p.Leu164Thrfs*27) in the SGCA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGCA are known to be pathogenic (PMID: 9192266). ClinVar contains an entry for this variant (Variation ID: 370116). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 24, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 27, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2019

The c.488dupG variant has been previously reported in an individual with limb-girdle weakness, calf hypertrophy, and elevated CK levels who harbored an additional SGCA variant (Klinge et al., 2008). The c.488dupG variant is not observed in large population cohorts (Lek et al., 2016). This variant causes a frameshift starting with codon Leucine 164, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 27 of the new reading frame, denoted p.Leu164ThrfsX27. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs763986788; hg19: chr17-48245831;