rs762412447

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_000232.5(SGCB):c.355A>T(p.Ile119Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,582 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I119N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

SGCB
NM_000232.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:5

Conservation

PhyloP100: 5.84

Variant links:

Genes affected

SGCB (HGNC:10806): (sarcoglycan beta) This gene encodes a member of the sarcoglycan family. Sarcoglycans are transmembrane components in the dystrophin-glycoprotein complex which help stabilize the muscle fiber membranes and link the muscle cytoskeleton to the extracellular matrix. Mutations in this gene have been associated with limb-girdle muscular dystrophy.[provided by RefSeq, Oct 2008]

SGCB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000232.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-52029751-A-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.877

PP5

Variant 4-52029752-T-A is Pathogenic according to our data. Variant chr4-52029752-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282249.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Pathogenic=1, Likely_pathogenic=3}. Variant chr4-52029752-T-A is described in Lovd as [Pathogenic]. Variant chr4-52029752-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCB	NM_000232.5 link	c.355A>T	p.Ile119Phe	missense_variant	Exon 3 of 6	ENST00000381431.10	NP_000223.1	Q16585-1Q5U0N0
SGCB	XM_047416074.1 link	c.145A>T	p.Ile49Phe	missense_variant	Exon 2 of 5		XP_047272030.1
SGCB	XM_047416075.1 link	c.58A>T	p.Ile20Phe	missense_variant	Exon 2 of 5		XP_047272031.1
SGCB	XM_047416076.1 link	c.58A>T	p.Ile20Phe	missense_variant	Exon 2 of 5		XP_047272032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10 link	c.355A>T	p.Ile119Phe	missense_variant	Exon 3 of 6	1	NM_000232.5	ENSP00000370839.6		Q16585-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251470

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461582

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727110

show subpopulations

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:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E

Pathogenic:3Uncertain:4

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.355A>T(p.Ile119Phe) variant in SGCB gene has been reported previously in homozygous, compound heterozygous and heterozygous state in individual(s) affected with muscular dystrophy (Fichna JP, et al., 2018; Monies D, et al., 2016; Mohammad NS, et al 2022; Duclos F, et al). The p.Ile119Phe variant has been reported with allele frequency of 0.02% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Uncertain Significance (multiple submissions). The amino acid change p.Ile119Phe in SGCB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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. However, provided evidence is insufficienct to make an independent assesment of pathogenicity. For these reaons, this variant has been classified as a Variant of Uncertain Significant (VUS). -

Oct 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SGCB protein function with a negative predictive value of 80%. 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. 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. -

Feb 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2021

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported in individuals affected with limb-girdle muscular dystrophy (as represented as p.I119F in the article) and was found to be absent in controls samples analyzed. This variant was classified as ‘pathogenic’ based on ACMG classification. [PMID: 9565988, 27671536, 29970176]. -

Oct 10, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

not provided

Pathogenic:1Uncertain:1

Feb 10, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on cell surface abundance and a non-functional protein product (PMID: 37317968); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9565988, 8968749, 30564623, 34925456, 29970176, 38876406, 39769077, 35416532, 39548682, 27671536, 37317968) -

Jun 12, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.77

MutationAssessor

Uncertain

2.2

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.1

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0050

Sift4G

Benign

0.21

Polyphen

0.92

Vest4

0.93

MutPred

0.63

Loss of catalytic residue at P121 (P = 0.0303);

MVP

1.0

MPC

0.37

ClinPred

0.53

GERP RS

5.3

Varity_R

0.30

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over