Submissions for variant NM_021625.5(TRPV4):c.958C>T (p.Arg320Ter)

gnomAD frequency: 0.00006  dbSNP: rs142902080

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000551761	SCV000646258	uncertain significance	Charcot-Marie-Tooth disease axonal type 2C	2022-08-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg320*) in the TRPV4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TRPV4 cause disease. This variant is present in population databases (rs142902080, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with TRPV4-related conditions (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 469047). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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.
Illumina Laboratory Services, Illumina	RCV001109833	SCV001267209	likely benign	Brachyrachia (short spine dysplasia)	2017-07-11	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001109834	SCV001267210	likely benign	Metatropic dysplasia	2017-07-11	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001109835	SCV001267211	likely benign	Neuronopathy, distal hereditary motor, autosomal dominant 8	2017-07-11	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001109836	SCV001267212	likely benign	Scapuloperoneal spinal muscular atrophy	2017-07-11	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001109837	SCV001267213	likely benign	Spondylometaphyseal dysplasia, Kozlowski type	2017-07-11	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000551761	SCV001271662	likely benign	Charcot-Marie-Tooth disease axonal type 2C	2017-07-11	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173240	SCV001336322	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001508337	SCV001714415	uncertain significance	not provided	2020-07-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002384176	SCV002695652	likely benign	Inborn genetic diseases	2019-11-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV001508337	SCV003821546	uncertain significance	not provided	2022-08-04	criteria provided, single submitter	clinical testing
Genesis Genome Database	RCV000856931	SCV000999495	uncertain significance	Charcot-Marie-Tooth disease type 4	2019-08-14	no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001508337	SCV001809076	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001508337	SCV001958790	uncertain significance	not provided		no assertion criteria provided	clinical testing