rs752338221
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_003476.5(CSRP3):c.255C>T(p.Gly85Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_003476.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251142Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135770
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461840Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727224
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: CSRP3 c.255C>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a cryptic 5' splicing donor site, and one predicts it weakens the canonical 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251142 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.255C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 Uncertain:1
This sequence change affects codon 85 of the CSRP3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CSRP3 protein. This variant is present in population databases (rs752338221, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CSRP3-related conditions. ClinVar contains an entry for this variant (Variation ID: 520272). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
not provided Uncertain:1
p.Gly85Gly (c.255C>T) in exon 4 of the CSRP3 gene (NM_003476.3) CRCh37 chr11:19209709 Given the limited evidence associating splice site variants in this gene with HCM and the lack of case data for this variant, we consider this variant to be of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The test was performed by Ambry. We have seen this variant in one person with HCM. This variant has not been reported in the literature. There are two splice site variants (in positions that might possibly abolish a splice site rather than introduce it) listed in ClinVar that are listed as variants of uncertain significance The Ambry report notes that although the variant does not change the amino acid at position 85, the BDGP and ESEfinder splice site prediction tools predict that it may create a cryptic splice donor site. Vafiadaki et al., 2014 reported an alternative splice variant of muscle lim protein, the protein encoded by the CSRP3 gene. They reported that this alternative isoform (MLP-b) lacks exons 3 and 4 and results in a frameshift and downstream truncation protein as well as an additional segment of unique amino acids. The function of the MLP-b isoform is unclear at this time. The variant was reported online in 4 of 138,428 individuals (MAF:0.0014%) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 2 of 9,432 individuals of East Asian descent (0.01% MAF), 1 of 15,390 individuals of South Asian descent (0.003% MAF), and 1 of 63,188 individuals of non-Finnish European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). -
Cardiovascular phenotype Uncertain:1
The c.255C>T variant (also known as p.G85G), located in coding exon 2, results from a C to T substitution at nucleotide position 255 of the CSRP3 gene. This nucleotide substitution does not change the amino acid at codon 85. Based on nucleotide sequence alignment, this position is not well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site; however, direct evidence is unavailable. 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