Submissions for variant NM_000232.5(SGCB):c.355A>T (p.Ile119Phe)

gnomAD frequency: 0.00002  dbSNP: rs762412447

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000315486	SCV000333607	uncertain significance	not provided	2017-06-12	criteria provided, single submitter	clinical testing
Invitae	RCV000531503	SCV000642380	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2E	2023-08-10	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 119 of the SGCB protein (p.Ile119Phe). This variant is present in population databases (rs762412447, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 9565988, 27671536, 34925456, 35416532). ClinVar contains an entry for this variant (Variation ID: 282249). 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 not expected to disrupt SGCB protein function. This variant disrupts the p.Ile119 amino acid residue in SGCB. Other variant(s) that disrupt this residue have been observed in individuals with SGCB-related conditions (PMID: 29970176), which suggests that this may be a clinically significant amino acid residue.
Counsyl	RCV000531503	SCV000791916	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2E	2017-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000315486	SCV001982766	uncertain significance	not provided	2021-10-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9565988, 8968749, 30564623, 27671536)
Fulgent Genetics, Fulgent Genetics	RCV000531503	SCV002777067	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2E	2022-02-24	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000531503	SCV003827633	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2E	2023-10-10	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000531503	SCV004047688	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2E		criteria provided, single submitter	clinical testing	The missense variant c.355A>T (p.Ile119Phe) in SGCB gene has been reported in individual(s) affected with muscular dystrophy (Monies D et.al.,2016) . This variant has been reported to the ClinVar database as Uncertain Significance. The p.Ile119Phe variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.00001988% is reported in gnomAD. The amino acid Ile at position 119 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ile119Phe in SGCB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000531503	SCV002601580	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2E		flagged submission	clinical testing	A heterozygous missense variation in exon 3 of the SGCB gene that results in the amino acid substitution of Phenylalanine for Isoleucine at codon 119 was detected.This variant has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.