10-119672373-C-T

Position:

• chr10-119672373-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_004281.4(BAG3):​c.626C>T​(p.Pro209Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P209P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BAG3 NM_004281.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 6.13

Genes affected

BAG3 (HGNC:939): (BAG cochaperone 3) BAG proteins compete with Hip for binding to the Hsc70/Hsp70 ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The protein encoded by this gene contains a WW domain in the N-terminal region and a BAG domain in the C-terminal region. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 10-119672373-C-T is Pathogenic according to our data. Variant chr10-119672373-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-119672373-C-T is described in Lovd as [Pathogenic]. Variant chr10-119672373-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAG3	NM_004281.4	c.626C>T	p.Pro209Leu	missense_variant	3/4	ENST00000369085.8	NP_004272.2
BAG3	XM_005270287.2	c.626C>T	p.Pro209Leu	missense_variant	3/4		XP_005270344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAG3	ENST00000369085.8	c.626C>T	p.Pro209Leu	missense_variant	3/4	1	NM_004281.4	ENSP00000358081.4
BAG3	ENST00000450186.1	c.452C>T	p.Pro151Leu	missense_variant	4/5	5		ENSP00000410036.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 6 Pathogenic:4 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as disease-causing and was found once in our laboratory as a de novo change in a 4-year-old male with muscular weakness, tight heel cords, restrictive cardiomyopathy. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 15, 2018	The heterozygous p.Pro209Leu variant was identified by our study in one individual with myofibrillar myopathy. Trio exome analysis showed this variant to be de novo. The p.Pro209Leu variant is pathogenic based off of our findings, multiple de novo reports in ClinVar, and the literature. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The missense variant c.626C>T (p.Pro209Leu) in the BAG3 gene has been reported previously in heterozygous state in individuals affected with myofibrillar myopathy and cardiomyopathy. Experimental studies have shown that this missense change affects protein function (Kimura et al., 2021; D'Avila et al., 2016). This variant is absent in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic (Multiple submitters). The amino acid Proline at position 209 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Pro209Leu in BAG3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2020	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23341456, 26545904, 21423662, 30105547, 29338979, 30384889, 27321750, 22734908, 25728519, 21898660, 21361913, 19085932, 28831623, 27443559, 30023292, 28224639, 30061062, 30145633, 29552495, 30499714, 30559338, 29405094, 25273835, 32472079, 32453099) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics laboratory, Necker Hospital	Jan 29, 2019	- -

Peripheral neuropathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Myofibrillar myopathy 6;C3151293:Dilated cardiomyopathy 1HH Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 209 of the BAG3 protein (p.Pro209Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with myofibrillar myopathy (PMID: 19085932, 20605452, 21361913, 22734908, 25208129, 25728519, 26545904, 27443559). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 5981). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BAG3 protein function. Experimental studies have shown that this missense change affects BAG3 function (PMID: 19085932, 21898660, 25273835, 27321750, 27443559). This variant disrupts the p.Pro209 amino acid residue in BAG3. Other variant(s) that disrupt this residue have been observed in individuals with BAG3-related conditions (PMID: 25208129, 27164712), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2022

The p.P209L pathogenic mutation (also known as c.626C>T), located in coding exon 3 of the BAG3 gene, results from a C to T substitution at nucleotide position 626. The proline at codon 209 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in numerous individuals with myofibrillar myopathy and was found to be de novo in these individuals (Selcen D et al. Ann Neurol, 2009 Jan;65:83-9; Jaffer F et al. J Peripher Nerv Syst, 2012 Jun;17:210-6; Lee HC et al. Clin Genet, 2012 Apr;81:394-8; Kostera-Pruszczyk A et al. J Muscle Res Cell Motil, 2015 Dec;36:423-32; Konersman CG et al. Neuromuscul Disord, 2015 May;25:418-22; D'Avila F et al. J Muscle Res Cell Motil, 2016 06;37:101-15; Vasilescu C et al. J Am Coll Cardiol, 2018 11;72:2324-2338; Andersen AG et al. Neuromuscul Disord, 2018 09;28:798-801; Schänzer A et al. Mol Genet Metab, 2018 03;123:388-399; Kim SJ et al. Genes Genomics, 2018 12;40:1269-1277; Noury JB et al. Muscle Nerve, 2018 02;57:330-334; Herman I et al. Muscle Nerve, 2021 03;63:304-310; Zhan L et al. Medicine (Baltimore), 2022 Jan;101:e28484). In vivo studies showed this alteration impacts protein function (Kimura K et al. Nat Commun, 2021 06;12:3575). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.84		Gain of sheet (P = 0.0266);.;
MVP		0.99
MPC		0.42
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.71
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs121918312; hg19: chr10-121431885; COSMIC: COSV64842767;