11-19188220-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_003476.5(CSRP3):āc.197A>Gā(p.Tyr66Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,398 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y66N) has been classified as Uncertain significance.
Frequency
Consequence
NM_003476.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CSRP3 | NM_003476.5 | c.197A>G | p.Tyr66Cys | missense_variant | 3/6 | ENST00000265968.9 | |
CSRP3 | NM_001369404.1 | c.113-1872A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CSRP3 | ENST00000265968.9 | c.197A>G | p.Tyr66Cys | missense_variant | 3/6 | 1 | NM_003476.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251298Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135808
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461398Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726998
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 21, 2012 | The Tyr66Cys variant in CSRP3 has been reported in one Caucasian individual with HCM that carried another likely pathogenic variant (Arg162Gln in TNNI3; Bos 200 6). This variant has not been identified in large and broad European American an d African American populations by the NHLBI Exome Sequencing Project (http://evs .gs.washington.edu/EVS). A presence in other populations cannot be excluded. Com putational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical signi ficance of the Tyr66Cys variant. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 27, 2019 | - - |
Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 24, 2023 | 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 44691). This missense change has been observed in individual(s) with cardiomyopathy (PMID: 16352453, 27532257). This variant is present in population databases (rs397516854, gnomAD 0.004%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 66 of the CSRP3 protein (p.Tyr66Cys). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 05, 2023 | Reported in a patient with hypertrophic cardiomyopathy; this patient was also heterozygous for a variant in the TNNI3 gene (Bos et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28867610, 35241752, 30012424, 36935760, 16352453, 27532257) - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 23, 2015 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 22, 2021 | The c.197A>G (p.Y66C) alteration is located in exon 3 (coding exon 2) of the CSRP3 gene. This alteration results from a A to G substitution at nucleotide position 197, causing the tyrosine (Y) at amino acid position 66 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at