Submissions for variant NM_000023.4(SGCA):c.518T>C (p.Leu173Pro)

gnomAD frequency: 0.00003  dbSNP: rs143962150

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000284145	SCV000331084	pathogenic	not provided	2015-12-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194148	SCV001363448	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2019-11-08	criteria provided, single submitter	clinical testing	Variant summary: SGCA c.518T>C (p.Leu173Pro) results in a non-conservative amino acid change in the encoded protein sequence. The variant is indicated to be located in a potential glycosylation site (Carrie_1997). 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 4.6e-05 in 193856 control chromosomes (gnomAD). c.518T>C has been reported in the literature in individuals affected with Limb-girdle muscular dystrophy, autosomal recessive (Carrie_1997, Duggan_1997, Trabelsi_2008). Trabelsi_2008 reports the compound heterozygote patient showed decreased protein levels for gamma-sarcoglycan and no protein expression for alpha-sarcoglycan. These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001377411	SCV001574738	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 173 of the SGCA protein (p.Leu173Pro). This variant is present in population databases (rs143962150, gnomAD 0.1%). This missense change has been observed in individual(s) with sarcoglycanopathy (PMID: 9032047, 18285821; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 281027). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000284145	SCV001778120	pathogenic	not provided	2020-05-15	criteria provided, single submitter	clinical testing	Observed in multiple patients who harbored a second SGCA variant with complete a-sarcoglycan deficiency (Duggan et al., 1997; Trabelsi et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9032047, 18285821, 24742800, 9192266)
Revvity Omics, Revvity	RCV001377411	SCV002019194	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2021-09-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001377411	SCV002060074	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2021-11-08	criteria provided, single submitter	clinical testing	NM_000023.2(SGCA):c.518T>C(L173P) is a missense variant classified as likely pathogenic in the context of alpha-sarcoglycanopathy. L173P has been observed in cases with relevant disease (PMID: 18285821, 9393893, 9032047). Functional assessments of this variant are not available in the literature. L173P has been observed in population frequency databases (gnomAD: ASJ 0.09%). In summary, NM_000023.2(SGCA):c.518T>C(L173P) 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.
Fulgent Genetics, Fulgent Genetics	RCV001377411	SCV002794388	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2022-01-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001377411	SCV003931676	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-02-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001377411	SCV004203154	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-10-19	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000284145	SCV004230053	likely pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.