ClinVar Miner

Submissions for variant NM_003476.4(CSRP3):c.131T>C (p.Leu44Pro) (rs104894205)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621095 SCV000740226 uncertain significance Cardiovascular phenotype 2018-04-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Center for Human Genetics,University of Leuven RCV000768501 SCV000886806 uncertain significance Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000627796 SCV000657461 likely pathogenic Familial hypertrophic cardiomyopathy 12; Dilated cardiomyopathy 1M 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 44 of the CSRP3 protein (p.Leu44Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hypertrophic cardiomyopathy in a single family (PMID: 18505755). This variant has also been reported in several unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 16352453, 22429680, 27532257, 25351510). However, in one of those individuals, a pathogenic allele was also identified in MYBPC3.  ClinVar contains an entry for this variant (Variation ID: 8778). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037770 SCV000061432 uncertain significance not specified 2012-08-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Leu44Pro variant in CSRP3 has been identified in 1 individual with HCM, was absent from 1000 control chromosomes and segregated with disease in 2 definitively and 1 possibly affected relatives as well as one obligate carrier with unknown disease status (Geier 2003; Geier 2008). This variant was absent from two large and broad European and African American populations screened by the NHLBI Exome Sequencing Project (; dbSNP rs104894205). The affected amino acid is highly conserved in evolution, suggesting that a change would impact the protein. Other computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) also suggest that the Leu44Pro variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this data supports that the Leu44Pro variant may be pathogenic but is insufficient to establish this with certainty.
OMIM RCV000009323 SCV000029541 pathogenic Familial hypertrophic cardiomyopathy 12 2003-03-18 no assertion criteria provided literature only

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