17-50167422-T-C

Position:

• chr17-50167422-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The ENST00000262018.8(SGCA):​c.92T>C​(p.Leu31Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,876 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L31L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SGCA ENST00000262018.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.0710

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]

SGCA (HGNC:):

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 1 benign, 6 uncertain in ENST00000262018.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 17-50167422-T-C is Pathogenic according to our data. Variant chr17-50167422-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50167422-T-C is described in Lovd as [Pathogenic]. Variant chr17-50167422-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCA	NM_000023.4	c.92T>C	p.Leu31Pro	missense_variant	2/10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.92T>C	p.Leu31Pro	missense_variant	2/8		NP_001129169.1
SGCA	NR_135553.2	n.128T>C		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.92T>C	p.Leu31Pro	missense_variant	2/10	1	NM_000023.4	ENSP00000262018.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727244

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: 0.00000899

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:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 31 of the SGCA protein (p.Leu31Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9032047, 12566530, 18285821, 29351619). ClinVar contains an entry for this variant (Variation ID: 550333). 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. Experimental studies have shown that this missense change affects SGCA function (PMID: 22095924, 29351619). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 27, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jun 30, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.68	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.83	N;N
REVEL	Uncertain	0.59
Sift	Benign	0.040	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		0.99	D;D
Vest4		0.52
MutPred		0.83		Gain of catalytic residue at P30 (P = 0.0186);Gain of catalytic residue at P30 (P = 0.0186);
MVP		0.99
MPC		0.55
ClinPred		0.41	T
GERP RS		3.3
Varity_R		0.23
gMVP		0.86

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: rs903823830; hg19: chr17-48244783;