17-50167430-C-A

Position:

• chr17-50167430-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000023.4(SGCA):​c.100C>A​(p.Arg34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R34C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.81

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 10 ACMG points.

• PM1: In a topological_domain Extracellular (size 266) in uniprot entity SGCA_HUMAN there are 108 pathogenic changes around while only 2 benign (98%) 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 chr17-50167430-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 17-50167430-C-A is Pathogenic according to our data. Variant chr17-50167430-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1498501.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCA	NM_000023.4	c.100C>A	p.Arg34Ser	missense_variant	2/10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.100C>A	p.Arg34Ser	missense_variant	2/8		NP_001129169.1
SGCA	NR_135553.2	n.136C>A		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.100C>A	p.Arg34Ser	missense_variant	2/10	1	NM_000023.4	ENSP00000262018	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 18, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg34 amino acid residue in SGCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7663524, 9032047, 22095924). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has not been reported in the literature in individuals with SGCA-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 34 of the SGCA protein (p.Arg34Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D
Eigen	Benign	0.16
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.74	N;N
REVEL	Pathogenic	0.71
Sift	Benign	0.12	T;T
Sift4G	Benign	0.12	T;T
Polyphen		1.0	D;P
Vest4		0.65
MutPred		0.78		Loss of methylation at R34 (P = 0.0204);Loss of methylation at R34 (P = 0.0204);
MVP		0.98
MPC		0.75
ClinPred		0.94	D
GERP RS		3.4
Varity_R		0.16
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-48244791;