Submissions for variant NM_003476.5(CSRP3):c.131T>C (p.Leu44Pro)

gnomAD frequency: 0.00006  dbSNP: rs104894205

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 va riant in CSRP3 has been identified in 1 individual with HCM, was absent from 100 0 control chromosomes and segregated with disease in 2 definitively and 1 possib ly affected relatives as well as one obligate carrier with unknown disease statu s (Geier 2003; Geier 2008). This variant was absent from two large and broad Eu ropean and African American populations screened by the NHLBI Exome Sequencing P roject (http://evs.gs.washington.edu/EVS; dbSNP rs104894205). The affected amino acid is highly conserved in evolution, suggesting that a change would impact th e protein. Other computational analyses (biochemical amino acid properties, Alig nGVGD, PolyPhen2, and SIFT) also suggest that the Leu44Pro variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, this data supports that the Leu44Pro variant may be pathoge nic but is insufficient to establish this with certainty.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627796	SCV000657461	pathogenic	Hypertrophic cardiomyopathy 12; Dilated cardiomyopathy 1M	2023-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 44 of the CSRP3 protein (p.Leu44Pro). This variant is present in population databases (rs104894205, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12642359, 18505755; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8778). 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. Experimental studies have shown that this missense change affects CSRP3 function (PMID: 27353086, 30048712). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000621095	SCV000740226	uncertain significance	Cardiovascular phenotype	2021-10-15	criteria provided, single submitter	clinical testing	The c.131T>C (p.L44P) alteration is located in exon 3 (coding exon 2) of the CSRP3 gene. This alteration results from a T to C substitution at nucleotide position 131, causing the leucine (L) at amino acid position 44 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Center for Human Genetics, University of Leuven	RCV000768501	SCV000886806	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001529867	SCV002502885	likely pathogenic	not provided	2022-02-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001529867	SCV003805421	uncertain significance	not provided	2023-02-14	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect; however, it is not known whether these findings are biological or clinically relevant in vivo (Lange et al., 2016; Ehsan et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 30012424, 22429680, 18505755, 26183555, 25179549, 19115046, 27353086, 30048712, 35241752, 16352453, 25351510, 33662488, 32105245, 34495297, 31919335, 33035702, 12642359, 31513939)
Institute of Human Genetics, University Hospital Muenster	RCV003231096	SCV003929475	likely pathogenic	See cases	2022-12-29	criteria provided, single submitter	clinical testing	ACMG categories: PS5,PM2,PP3,PP5
KardioGenetik, Herz- und Diabeteszentrum NRW	RCV000009323	SCV005050135	likely pathogenic	Hypertrophic cardiomyopathy 12	2024-04-17	criteria provided, single submitter	clinical testing
OMIM	RCV000009323	SCV000029541	pathogenic	Hypertrophic cardiomyopathy 12	2003-03-18	no assertion criteria provided	literature only
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000009323	SCV001192742	likely pathogenic	Hypertrophic cardiomyopathy 12	2019-06-25	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529867	SCV001744072	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001529867	SCV001932185	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529867	SCV001955447	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529867	SCV001964251	likely pathogenic	not provided		no assertion criteria provided	clinical testing