rs786204485

chr17-50167644-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000023.4(SGCA):c.220C>T(p.Arg74Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R74Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.550

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 16 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000023.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-50167645-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1482622.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 17-50167644-C-T is Pathogenic according to our data. Variant chr17-50167644-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50167644-C-T is described in Lovd as [Pathogenic]. Variant chr17-50167644-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCA	NM_000023.4	c.220C>T	p.Arg74Trp	missense_variant	3/10	ENST00000262018.8
SGCA	NM_001135697.3	c.220C>T	p.Arg74Trp	missense_variant	3/8
SGCA	NR_135553.2	n.256C>T		non_coding_transcript_exon_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCA	ENST00000262018.8	c.220C>T	p.Arg74Trp	missense_variant	3/10	1	NM_000023.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250198 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135380

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461630 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727128

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000165 AC: 2

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 20, 2023	For these reasons, this variant has been classified as Pathogenic. 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 SGCA protein function. ClinVar contains an entry for this variant (Variation ID: 188811). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 9455986, 10993494, 15833425, 18285821, 24464767, 30345904; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. 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 replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 74 of the SGCA protein (p.Arg74Trp). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 15, 2021	NM_000023.2(SGCA):c.220C>T(R74W) is a missense variant classified as likely pathogenic in the context of alpha-sarcoglycanopathy. R74W has been observed in cases with relevant disease (PMID: 10993494, 18285821, 9455986, 30345904, 31069529, 29382405). Functional assessments of this variant are not available in the literature. R74W has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, NM_000023.2(SGCA):c.220C>T(R74W) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 17, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 30, 2023

Variant summary: SGCA c.220C>T (p.Arg74Trp) results in a non-conservative amino acid change located in the Dystroglycan-type cadherin-like domain (IPR006644) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250198 control chromosomes (gnomAD). c.220C>T has been reported in the literature in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Higuchi_1997, Trabelsi_2008, Saha_2018, Ganapathy_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30345904, 9455986, 31069529, 18285821). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Benign	0.059
Eigen_PC	Benign	-0.072
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.85		Gain of catalytic residue at L72 (P = 0.0312);Gain of catalytic residue at L72 (P = 0.0312);
MVP		0.99
MPC		1.0
ClinPred		0.95	D
GERP RS		1.2
Varity_R		0.12
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs757888349; hg19: chr17-48245005;