rs145300736
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_003476.5(CSRP3):c.148G>A(p.Ala50Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,612,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A50V) has been classified as Likely pathogenic.
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
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152122Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 250998Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135652
GnomAD4 exome AF: 0.0000438 AC: 64AN: 1460532Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37AN XY: 726574
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152122Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74322
ClinVar
Submissions by phenotype
not provided Uncertain:2
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Dilated cardiomyopathy 1M;C2677491:Hypertrophic cardiomyopathy 12 Uncertain:2
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 50 of the CSRP3 protein (p.Ala50Thr). This variant is present in population databases (rs145300736, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 20474083, 27532257). ClinVar contains an entry for this variant (Variation ID: 44687). 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 tolerated. 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. -
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CSRP3-related disorder Uncertain:1
The CSRP3 c.148G>A variant is predicted to result in the amino acid substitution p.Ala50Thr. This variant was reported in individuals with dilated cardiomyopathy (Zimmerman et al. 2010. PubMed ID: 20474083; Table S1B, Walsh et al. 2016. PubMed ID: 27532257) and also documented in the general population (Andreasen et al. 2013. PubMed ID: 23299917). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/44687). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The Ala50Thr varian t has not been identified in 1 individual with DCM out of >350 Caucasian individ uals tested and was absent from 344 Caucasian and 376 Black control chromosomes tested by our laboratory (Zimmerman 2010). Alanine (Ala) at position 50 is highl y conserved across evolutionarily distant species, suggesting that a change may negatively impact the protein's function, though fruitfly carries a threonine (t he same amino acid as this variant) and C. elegans carries a cystine. While cons ervation and absence in controls support a pathogenic role of the Ala50Thr varia nt, it was absent in an affected family member, which raises the possibility tha t it is benign. In summary, additional data is needed to clarify the clinical s ignificance of this variant. -
Cardiovascular phenotype Uncertain:1
The c.148G>A (p.A50T) alteration is located in exon 3 (coding exon 2) of the CSRP3 gene. This alteration results from a G to A substitution at nucleotide position 148, causing the alanine (A) at amino acid position 50 to be replaced by a threonine (T). 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