Submissions for variant NM_144573.4(NEXN):c.1112C>T (p.Pro371Leu)

dbSNP: rs200067011

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041157	SCV000064848	uncertain significance	not specified	2012-02-13	criteria provided, single submitter	clinical testing	The Pro371Leu variant (NEXN) has not been reported in the literature nor previou sly identified by our laboratory. Computational 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 need ed to fully assess the clinical significance of the Pro371Leu variant.
GeneDx	RCV000766516	SCV000236128	uncertain significance	not provided	2022-11-10	criteria provided, single submitter	clinical testing	Reported in association with HCM and DCM (Walsh et al., 2017; Mazzarotto et al., 2020); 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: 31983221, 27532257)
Blueprint Genetics	RCV000183659	SCV000264125	uncertain significance	Cardiomyopathy	2015-07-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471176	SCV000549231	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 371 of the NEXN protein (p.Pro371Leu). This variant is present in population databases (rs200067011, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 27532257, 31983221). ClinVar contains an entry for this variant (Variation ID: 47887). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NEXN protein function. 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253104	SCV001428636	uncertain significance	Hypertrophic cardiomyopathy 20	2018-03-29	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000183659	SCV002043700	uncertain significance	Cardiomyopathy	2019-11-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000471176	SCV002813411	uncertain significance	Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20	2021-10-29	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993773	SCV004812327	uncertain significance	Primary dilated cardiomyopathy	2023-08-01	criteria provided, single submitter	clinical testing	This sequence change in NEXN is predicted to replace proline with leucine at codon 371, p.(Pro371Leu). The proline residue is highly conserved (100 vertebrates, UCSC), and is not located in an annotated domain. There is a moderate physicochemical difference between proline and leucine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.01% (13/112594 alleles) in the European (non-Finnish) population. This variant has been reported in at least one individual with dilated cardiomyopathy but was also identified in a healthy control in the same study (PMID: 31983221). Computational evidence is uninformative for the missense substitution (REVEL = 0.519). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none.
Ambry Genetics	RCV004018906	SCV004985716	uncertain significance	Cardiovascular phenotype	2021-11-16	criteria provided, single submitter	clinical testing	The c.1112C>T (p.P371L) alteration is located in exon 10 (coding exon 9) of the NEXN gene. This alteration results from a C to T substitution at nucleotide position 1112, causing the proline (P) at amino acid position 371 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766516	SCV001741985	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000766516	SCV001923463	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000766516	SCV001930959	uncertain significance	not provided		no assertion criteria provided	clinical testing