ClinVar Genomic variation as it relates to human health

The GLMN c.157_161delAAGAA variant (rs762515373) is one of a common variants associated with glomuvenous malformations (Brouillard 2002, Brouillard 2005, Suárez-Magdalena 2019). These reports demonstrated segregation of this variant with disease from over 20 families, and with similar haplotype sharing suggestive of a common ancestral origin. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.02 percent in the South Asian population (identified on 6 out of 30,610 chromosomes) and has been reported to the ClinVar database as pathogenic (Variation ID: 7806). This variant causes a frameshift by deleting 5 nucleotides in the third exon (of 19 total exons), and is predicted to result in a truncated protein. Truncating variants in GLMN are a common mechanism of disease. Based on these observations, the c.157_161del is considered to be pathogenic. Pathogenic variants in GLMN are inherited in an autosomal dominant manner and are associated with glomuvenous malformations (MIM: 138000). Reduced penetrance and phenotypic variability are thought to be accounted for by somatic second hit variants, most commonly uniparental isodisomy involving chromosome 1p (Amyere 2013). References: Amyere et al. Somatic uniparental isodisomy explains multifocality of glomuvenous malformations. Am J Hum Genet. 2013 Feb 7;92(2):188-96. doi: 10.1016/j.ajhg.2012.12.017. Epub 2013 Jan 31. Brouillard et al. Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations ("glomangiomas"). Am J Hum Genet. 2002 Apr;70(4):866-74. Brouillard et al. Four common glomulin mutations cause two thirds of glomuvenous malformations ("familial glomangiomas"): evidence for a founder effect. J Med Genet. 2005 Feb;42(2):e13. Suárez-Magdalena et al., Glomulin gene c.157_161del mutation in a family with multiple glomuvenous malformations. Int J Dermatol. 2019 Feb;58(2):e43-e45.

The c.157_161delAAGAA (p.Lys53*) variant is one of the most frequently reported pathogenic GLMN variants, accounting for ~45% of affected individuals (Ref 1-3). The deletion of five nucleotides replaces the lysine with a premature stop codon at position 53 (p.Lys53*). This variant is predicted to result in a loss of gene function.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glomuvenous malformations (MIM#138000). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (14 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals and is the most common variant in the GLMN gene associated with glomuvenous malformations (ClinVar, PMID: 23801931). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30325312, 23801931, 11845407, 30460983, 32538359, 11175297, 31589614)

This sequence change in GLMN is a frameshift variant predicted to cause a premature stop codon, p.(Lys53*), in biologically relevant exon 3/19 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.02% (6/30,610 alleles) in the South Asian population. This variant is the most commonly reported variant causing glomuvenous malformations (PMID: 23801931), and segregates with disease in multiple families (PMID: 11845407, 30460983). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong.

The c.157_161delAAGAA (p.K53*) alteration, located in exon 3 (coding exon 2) of the GLMN gene, consists of a deletion of 5 nucleotides from position 157 to 161, causing a translational frameshift with a predicted alternate stop codon after amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.005% (14/282026) total alleles studied. The highest observed frequency was 0.02% (6/30610) of South Asian alleles. This variant has been reported in multiple individuals with glomuvenous malformations and has been to show to segregate with the phenotype in multiple large families (Brouillard, 2002; Brouillard, 2013; Su&aacute;rez-Magdalena, 2019). Based on the available evidence, this alteration is classified as pathogenic.

The GLMN c.157_161del5 variant is predicted to result in premature protein termination (p.Lys53*). This variant has been reported to be causative for autosomal dominant glomuvenous malformations in multiple families (referred to as 157delAAGAA - Brouillard et al. 2002. PubMed ID: 11845407). This variant is reported in 0.019% of alleles in individuals of South Asian in gnomAD. Loss-of-function variants in GLMN are a known cause of disease (Brouillard et al. 2013. PubMed ID: 23801931). This variant is interpreted as pathogenic.