rs137852621

chr17-50167717-G-Achr17-50167717-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_000023.4(SGCA):c.293G>A(p.Arg98His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,611,678 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R98P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 1.20

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 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr17-50167716-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 284708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 17-50167717-G-A is Pathogenic according to our data. Variant chr17-50167717-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50167717-G-A is described in Lovd as [Pathogenic]. Variant chr17-50167717-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-50167717-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCA	NM_000023.4	c.293G>A	p.Arg98His	missense_variant	3/10	ENST00000262018.8
SGCA	NM_001135697.3	c.293G>A	p.Arg98His	missense_variant	3/8
SGCA	NR_135553.2	n.329G>A		non_coding_transcript_exon_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCA	ENST00000262018.8	c.293G>A	p.Arg98His	missense_variant	3/10	1	NM_000023.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000203 AC: 5 AN: 246232 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133370

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000453

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1459378 Hom.: 0 Cov.: 32 AF XY: 0.0000221 AC XY: 16 AN XY: 725596

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: 0.0000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000389 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Pathogenic:9

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 26, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 26, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 28, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The missense c.293G>A (p.Arg98His) variant in SGCA gene has been reported in homozygous and compound heterozygous states in multiple individuals affected with muscular dystrophy (Fayssoil et al., 2016; Ljunggren et al., 1995). Experimental studies have shown that this missense change affects SGCA function (Gastaldello et al., 2008). This variant is reported with allele frequency of 0.002% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg98His in SGCA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 98 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. In absence of another reportable variant in SGCA gene, the molecular diagnosis is not confirmed. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 98 of the SGCA protein (p.Arg98His). This variant is present in population databases (rs137852621, gnomAD 0.004%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 7668821, 8069911, 9192266, 12746421, 22095924, 27120200). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9435). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SGCA function (PMID: 18535179, 22095924). For these reasons, this variant has been classified as Pathogenic. -
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

Oct 02, 2022

Variant summary: SGCA c.293G>A (p.Arg98His) results in a non-conservative amino acid change located in the Dystroglycan-type cadherin-like domain (IPR006644) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246232 control chromosomes. c.293G>A has been reported in the literature as biallelic genotypes in multiple individuals affected with features of Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Eymard_1997, Wu_2018, Pagola-Lorz_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Gastaldello_2008). The most pronounced variant effect results in decreased expression of this alpha-Sarcoglycan mutant in beta-gamma-delta-HEK cells that could be rescued by the proteasomal inhibitor MG132 treatment. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Benign	0.015
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.000050	A;A;A;A
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.96	N;N
REVEL	Uncertain	0.60
Sift	Benign	0.11	T;T
Sift4G	Benign	0.13	T;T
Polyphen		1.0	D;D
Vest4		0.31
MVP		1.0
MPC		0.44
ClinPred		0.36	T
GERP RS		3.5
Varity_R		0.054
gMVP		0.73

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: rs137852621; hg19: chr17-48245078; COSMIC: COSV56251066; COSMIC: COSV56251066;