rs397517236
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_014000.3(VCL):āc.1798A>Cā(p.Ser600Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. S600S) has been classified as Likely benign.
Frequency
Consequence
NM_014000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VCL | NM_014000.3 | c.1798A>C | p.Ser600Arg | missense_variant | 13/22 | ENST00000211998.10 | |
VCL | NM_003373.4 | c.1798A>C | p.Ser600Arg | missense_variant | 13/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VCL | ENST00000211998.10 | c.1798A>C | p.Ser600Arg | missense_variant | 13/22 | 1 | NM_014000.3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251446Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135898
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461786Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727198
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 29, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 16, 2010 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2013 | p.Ser600Arg (AGC>CGC): c.1798 A>C in exon 13 of the VCL gene (NM_014000.2). The Ser600Arg variant in the VCL gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ser600Arg results in a semi-conservative amino acid substitution of a neutral, polar Serine to a positively-charged Arginine at a position that is highly conserved across species. In silico analysis predicts Ser600Arg is damaging to the protein structure/function. The Ser600Arg variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, very few missense mutations in the VCL gene have been reported, and none of these reported mutations are near Ser600Arg, indicating this region of the protein may tolerate change.With the clinical and molecular information available at this time, we cannot definitively determine if Ser600Arg is a disease-causing mutation or a rare benign variant. The variant is found in DCM panel(s). - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 22, 2016 | - - |
Dilated cardiomyopathy 1W Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2023 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 45591). This missense change has been observed in individual(s) with clinical features of left ventricular noncompaction (PMID: 33500567). This variant is present in population databases (rs397517236, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 600 of the VCL protein (p.Ser600Arg). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at