chr11-19192356-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_003476.5(CSRP3):c.93C>G(p.His31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,746 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 Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
CSRP3
NM_003476.5 missense
NM_003476.5 missense
Scores
11
6
1
Clinical Significance
Conservation
PhyloP100: 3.46
Genes affected
CSRP3 (HGNC:2472): (cysteine and glycine rich protein 3) This gene encodes a member of the CSRP family of LIM domain proteins, which may be involved in regulatory processes important for development and cellular differentiation. The LIM/double zinc-finger motif found in this protein is found in a group of proteins with critical functions in gene regulation, cell growth, and somatic differentiation. Mutations in this gene are thought to cause heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) in humans. Alternatively spliced transcript variants with different 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a domain LIM zinc-binding 1 (size 51) in uniprot entity CSRP3_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_003476.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.967
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CSRP3 | NM_003476.5 | c.93C>G | p.His31Gln | missense_variant | 2/6 | ENST00000265968.9 | |
CSRP3 | NM_001369404.1 | c.93C>G | p.His31Gln | missense_variant | 2/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CSRP3 | ENST00000265968.9 | c.93C>G | p.His31Gln | missense_variant | 2/6 | 1 | NM_003476.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461746Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727196
GnomAD4 exome
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4
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1461746
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31
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3
AN XY:
727196
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 20, 2019 | This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 28790153). ClinVar contains an entry for this variant (Variation ID: 217825). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with glutamine at codon 31 of the CSRP3 protein (p.His31Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 20, 2023 | The p.H31Q variant (also known as c.93C>G), located in coding exon 1 of the CSRP3 gene, results from a C to G substitution at nucleotide position 93. The histidine at codon 31 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in an individual from a hypertrophic cardiomyopathy cohort (Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hypertrophic cardiomyopathy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Aug 06, 2015 | The His31Gln variant in CSRP3 has not previously been reported in individuals with cardiomyopathy and is absent in both the 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified this variant in 1 HCM proband in our cohort who has septal wall thickness of 21mm and severe obstruction. Computational analyses (Polyphen-2, Mutation Taster, SIFT and CADD) suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of the His31Gln variant therefore we classify this variant as a variant of 'uncertain significance'. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;.;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;H;H;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;.;D;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;.;D;.
Sift4G
Pathogenic
D;.;.;.;D;.
Polyphen
D;.;.;D;D;.
Vest4
MutPred
Gain of catalytic residue at H31 (P = 0.1264);Gain of catalytic residue at H31 (P = 0.1264);Gain of catalytic residue at H31 (P = 0.1264);Gain of catalytic residue at H31 (P = 0.1264);Gain of catalytic residue at H31 (P = 0.1264);Gain of catalytic residue at H31 (P = 0.1264);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at