Submissions for variant NM_000231.3(SGCG):c.525del (p.Phe175fs)

dbSNP: rs786204786

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000169675	SCV000221211	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2014-09-15	criteria provided, single submitter	clinical testing	The Phe175LeufsX20 variant in SGCG has been reported in many individuals with limb girdle muscular dystrophy type 2C (LGMD2C; Noguchi 1995, Boyden 2010, Herson 2012, Schroder 2014, El Kerch 2014). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 175 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete loss of SGCG function is an established disease mechanism in LGMD2C. In summary, this variant meets our criteria to be classified as pathogenic for LGMD2C in an autosomal recessive manner.
Eurofins Ntd Llc (ga)	RCV000713258	SCV000331677	pathogenic	not provided	2016-08-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169675	SCV000634388	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe175Leufs*20) in the SGCG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGCG are known to be pathogenic (PMID: 18285821). This variant is present in population databases (rs765500509, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with limb girdle muscular dystrophy (PMID: 7481775, 12040521, 22240777, 23929688, 24552312). ClinVar contains an entry for this variant (Variation ID: 189243). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000713258	SCV000843846	pathogenic	not provided	2014-12-19	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. Found in multiple individuals with expected phenotype for this gene.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000169675	SCV001164546	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2018-12-03	criteria provided, single submitter	research	The homozygous p.Phe175LeufsTer20 variant in SGCG was identified by our study in five individuals (four siblings and one unrelated individual) with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.006092% (15/246240) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs765500509). Although this variant has been seen in the general population, the frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 175 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SGCG gene is an established disease mechanism in autosomal recessive LGMD. This variant has also been reported in ClinVar (Variation ID: 189243). In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and multiple reports in ClinVar. ACMG/AMP Criteria applied: PM2, PVS1, PP1 (Richards 2015).
CeGaT Center for Human Genetics Tuebingen	RCV000713258	SCV001245659	pathogenic	not provided	2016-09-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000713258	SCV001792557	pathogenic	not provided	2021-12-29	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11693784, 18285821, 22367371, 17994539, 16832103, 23929688, 7481775, 16616845, 15954112, 14678800, 26404900, 25252238, 16916601, 22240777, 24552312, 12040521, 27759885, 30919934, 31130284, 31980526, 31127727, 8900232, 20623375, 19770540, 10942431, 32214227, 25214167, 32528171, 31589614)
Revvity Omics, Revvity	RCV000169675	SCV002021240	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2023-06-30	criteria provided, single submitter	clinical testing
3billion	RCV000169675	SCV002521573	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000189243 / PMID: 7481775). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000169675	SCV002579640	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2021-11-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169675	SCV002789251	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2021-07-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169675	SCV004201034	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2024-03-14	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000169675	SCV004806503	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2024-03-26	criteria provided, single submitter	clinical testing
Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire	RCV004586589	SCV005038501	likely pathogenic	SGCG-related congenital myopathy	2024-03-01	criteria provided, single submitter	research	PVS1+PM2
OMIM	RCV000169675	SCV000022239	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2000-08-12	no assertion criteria provided	literature only
Counsyl	RCV000169675	SCV001132481	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2017-02-22	no assertion criteria provided	clinical testing
Section for Clinical Neurogenetics, University of Tübingen	RCV000169675	SCV001156104	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2019-08-01	no assertion criteria provided	research
Natera, Inc.	RCV000169675	SCV001455353	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2020-09-16	no assertion criteria provided	clinical testing