Submissions for variant NM_000231.3(SGCG):c.195+4_195+7del

dbSNP: rs797045106

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000190623	SCV000245659	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2014-12-30	criteria provided, single submitter	clinical testing	The c.195+4_195+7del variant in SGCG has been reported in 1 homozygous and 2 compound heterozygous individuals with limb girdle muscular dystrophy type 2C (LGMD2C; Bonnemann 2002). This variant has also been identified in 1/8254 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is a deletion of 4 nucleotides in the 5' splice region and in vitro functional assays suggest that this variant leads to altered splicing and the inclusion of an additional 16 nucleotides (Bonnemann 2002), which is predicted to lead to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic for LGMD2C in an autosomal recessive manner (http://pcpgmwww.partners.org/personalizedmedicince/LMM ).
Eurofins Ntd Llc (ga)	RCV000713256	SCV000331265	pathogenic	not provided	2017-12-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000190623	SCV000634381	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change falls in intron 2 of the SGCG gene. It does not directly change the encoded amino acid sequence of the SGCG protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs758531560, gnomAD 0.004%). This variant has been observed in individuals with limb-girdle muscular dystrophy (PMID: 11801399, 17897828, 19770540). This variant is also known as c.195+2_5del. ClinVar contains an entry for this variant (Variation ID: 208611). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in a 16-bp intronic insertion and introduces a premature termination codon (PMID: 11801399). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000713256	SCV000843844	pathogenic	not provided	2017-09-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000190623	SCV002021236	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2022-12-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000190623	SCV002048258	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2021-04-23	criteria provided, single submitter	clinical testing	The SGCG c.195+4_195+7delAGTA variant (rs797045106), also published as del 4-bp intron 2 or 195+2_5del, is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with limb-girdle muscular dystrophy or a sarcoglycanopathy (Bonnemann 2002, Khadilkar 2009, Reddy 2017). This variant is found on only three chromosomes (3/282718 alleles) in the Genome Aggregation Database. This is an intronic variant in that deletes four conserved nucleotides, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Consistent with these predictions, RNA studies of patients with this variant demonstrate use of cryptic splice donor site downstream, resulting in a 16 nucleotide insertion that leads to a frameshift (Bonnemann 2002). Based on available information, this variant is considered to be pathogenic. References: Bonnemann et al., Primary gamma-sarcoglycanopathy (LGMD 2C): broadening of the mutational spectrum guided by the immunohistochemical profile. Neuromuscul Disord. 2002 Mar;12(3):273-80. PMID: 11801399. Khadilkar SV et al. Spectrum of mutations in sarcoglycan genes in the Mumbai region of western India: high prevalence of 525del T. Neurol India. 2009 Jul-Aug;57(4):406-10. PMID: 19770540. Reddy et al., The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. J Hum Genet. 2017 Feb;62(2):243-252. PMID: 27708273.
Fulgent Genetics, Fulgent Genetics	RCV000190623	SCV002809929	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2021-10-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000190623	SCV004201042	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2024-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000713256	SCV005324947	pathogenic	not provided	2023-08-29	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in loss of function due to aberrant splicing leading to the generation of a premature stop codon predicted to result in nonsense mediated decay or protein truncation (Bnnemann et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 31589614, 19781108, 27708273, 17897828, 11801399, 19770540, 30564623)
Counsyl	RCV000190623	SCV000485728	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2016-11-11	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000190623	SCV001455343	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2C	2020-09-16	no assertion criteria provided	clinical testing