10-74082499-C-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_014000.3(VCL):c.829C>A(p.Leu277Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000948 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L277L) has been classified as Benign.
Frequency
Consequence
NM_014000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251460Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135906
GnomAD4 exome AF: 0.0000937 AC: 137AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.0000894 AC XY: 65AN XY: 727228
GnomAD4 genome AF: 0.000105 AC: 16AN: 152330Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74486
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 15 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 07, 2006 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 23, 2021 | - - |
Dilated cardiomyopathy 1W Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2025 | This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 277 of the VCL protein (p.Leu277Met). This variant is present in population databases (rs71579353, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 16712796, 24503780, 27930701, 31513939). ClinVar contains an entry for this variant (Variation ID: 12198). 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 tolerated. 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. - |
Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 22, 2021 | - - |
Primary familial dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 05, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 24503780, 25179549, 28218286, 24062880, 17097056, 27957775, 27930701, 31513939, 29875424, 16712796, 28771489) - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Oct 31, 2018 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 25, 2024 | The c.829C>A (p.L277M) alteration is located in exon 7 (coding exon 7) of the VCL gene. This alteration results from a C to A substitution at nucleotide position 829, causing the leucine (L) at amino acid position 277 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 06, 2022 | Variant summary: VCL c.829C>A (p.Leu277Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 251860 control chromosomes. The observed variant frequency is approximately 4.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.829C>A has been reported in the literature in at-least one individual with hypertrophic cardiomyopathy (HCM) and continues to be reported as a VUS in settings of multigene panel testing among cohorts of affected individuals with dilated cardiomyopathy (DCM), sudden cardiac death (SCD) and HCM (example, Vasile_2006, Pugh_2014, Sanchez_2016, Mazzarotto_2019, Robyns_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at