rs104894204
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_003476.5(CSRP3):c.172T>G(p.Cys58Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,086 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 (★). Synonymous variant affecting the same amino acid position (i.e. C58C) has been classified as Likely benign.
Frequency
Consequence
NM_003476.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CSRP3 | NM_003476.5 | c.172T>G | p.Cys58Gly | missense_variant | 3/6 | ENST00000265968.9 | |
CSRP3 | NM_001369404.1 | c.113-1897T>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CSRP3 | ENST00000265968.9 | c.172T>G | p.Cys58Gly | missense_variant | 3/6 | 1 | NM_003476.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461086Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726844
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 12 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 15, 2008 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2019 | The p.C58G variant (also known as c.172T>G), located in coding exon 2 of the CSRP3 gene, results from a T to G substitution at nucleotide position 172. The cysteine at codon 58 is replaced by glycine, an amino acid with highly dissimilar properties. This variant has been reported to segregate with hypertrophic cardiomyopathy in a single large German family (Geier C et al. Circulation, 2003 Mar;107:1390-5; Geier C et al. Hum. Mol. Genet., 2008 Sep;17:2753-65). In vitro functional studies suggest C58G disrupts protein function, and mice homozygous for a knock-in C58G allele develop cardiomyopathy and exhibit severely decreased levels of CSRP3 protein; however, heterozygous knock-in mice are unaffected and the physiological relevance of the in vitro results is unclear (Janin A et al. Gene, 2018 Nov;676:110-116; Ehsan M et al. J. Mol. Cell. Cardiol., 2018 Aug;121:287-296). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at