ClinVar Genomic variation as it relates to human health

The VCL c.2862_2864del; p.Leu955del variant (rs397517237) is reported in the literature in three individuals who were diagnosed with cardiomyopathy or hyperdynamic left ventricular function (Ng 2013, Olson 2002, and Walsh 2017); however, inheritance and detailed clinical information were not reported for these individuals. This variant deletes a single leucine residue leaving the rest of the protein in-frame. While functional studies demonstrate that the p.Leu955del variant alters actin filament organization, the clinical relevance of these observations is unclear (Olson 2002). The p.Leu955del variant found in the African population with an allele frequency of 0.45% (112/24974 alleles, including a single homozygote) in the Genome Aggregation Database, and is listed in ClinVar with conflicting interpretations of pathogenicity (Variation ID: 45602). Therefore, based on the available information, the clinical significance of the p.Leu955del variant cannot be determined with certainty. References: Ng et al. Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. Olson et al. Metavinculin mutations alter actin interaction in dilated cardiomyopathy. Circulation. 2002 Jan 29;105(4):431-7. Walsh et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203.

This variant is associated with the following publications: (PMID: 24062880, 11815424, 27532257, 24503780, 23861362, 16236538)

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.

Variant summary: VCL c.2862_2864delGTT (p.Leu955del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 0.0004 in 278208 control chromosomes, predominantly at a frequency of 0.0045 within the African subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African control individuals in the gnomAD database is approximately 180-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in VCL causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant, c.2862_2864delGTT, has been reported in the literature in individuals affected with Cardiomyopathy (Ng_2013, Olson_2002, Walsh_2017, Pugh_DSC2_GIM_2014). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Olson_2002). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign x4, VUS x1, benign x1). Based on the evidence outlined above, the variant was classified as likely benign.

p.Leu955del in exon 19 of VCL: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (50/10406) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs397517237).

VCL NM_014000.2 exon 19 p.Leu955del (c.2862_2864del): This variant has been reported in the literature in two individuals with DCM (Olson 2002 PMID:11815424, Walsh 2017 PMID:27532257). However, this variant is also present in 0.4% (112/24974) of African alleles in the Genome Aggregation Database, including one homozygote (http://gnomad.broadinstitute.org/variant/10-75871781-CTGT-C) and is present in ClinVar, with several labs classifying this variant as benign or likely benign (Variation ID:45602). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. An in vitro functional study predicted that this variant may impact the protein (Olson 2002 PMID:11815424). However, this study may not accurately represent in vivo biological function. This variant represents an in-frame deletion of one amino acid at position 955 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

The VCL p.Leu955del variant was identified in 2 of 2440 proband chromosomes (frequency: 0.00082) from individuals or families with arrhythmia, cardiomyopathy, or a family history of sudden death and was not identified in 1000 control chromosomes from healthy individuals (Olson_2002_PMID:11815424; Ng_2013_PMID:23861362). The variant was also identified in dbSNP (ID: rs397517237) and ClinVar (classified as a VUS by three submitters, likely benign by five submitters and benign by Invitae ) but was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 115 of 282866 chromosomes (1 homozygous) at a frequency of 0.000407 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 112 of 24974 chromosomes (freq: 0.004485), Other in 1 of 7226 chromosomes (freq: 0.000138) and Latino in 2 of 35440 chromosomes (freq: 0.000056), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), or South Asian populations. This variant is an in-frame deletion resulting in the removal of a leucine (leu) residue at codon 955; the impact of this alteration on VCL protein function is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.