ClinVar Genomic variation as it relates to human health

The GPSM2 c.742delC (p.Gly249GlufsTer32) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Gly249GlufsTer32 variant has been reported in two studies in which it is found in a total of seven individuals with Chudley-McCullough syndrome (CMS) from four families, including in three individuals carrying the variant in a homozygous state (two siblings and one unrelated individual) and four carrying the variant in a compound heterozygous state (two pairs of siblings) (Doherty et al. 2012; Diaz-Horta et al. 2012). The p.Gly249GlufsTer32 variant was also found in a heterozygous state in two unaffected family members (Diaz-Horta et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.000363 in the European American population of the Exome Sequencing Project. Based on the evidence and potential impact of frameshift variants, the p.Gly249GlufsTer32 variant is classified as likely pathogenic for GPSM2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The p.Gly249fs variant in GPSM2 has been reported in 3 individuals with Chudley- McCullough syndrome (Doherty 2012). Two of these individuals and one of their si blings were homozygous and 1 individual and a sibling were compound heterozygous . This variant is predicted to cause a frameshift, which alters the protein?s am ino acid sequence beginning at position 249 and leads to a premature termination codon 32 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss-of-function variants in the GPSM2 gene are as sociated with Chudley-McCullough syndrome, an autosomal recessive condition with congenital hearing loss and brain abnormalities with typically normal cognition . In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive Chudley-McCullough syndrome.

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 Chudley-McCullough syndrome (MIM#604213). (I) 0106 - This gene is associated with autosomal recessive 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) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (28 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other loss of function variants have previously been reported as pathogenic in individuals with Chudley-McCullough syndrome (MIM#604213) (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple individuals with Chudley-McCullough syndrome (MIM#604213) (ClinVar, LOVD, PMID: 22987632). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This sequence change creates a premature translational stop signal (p.Gly249Glufs*32) in the GPSM2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GPSM2 are known to be pathogenic (PMID: 22578326, 22987632). This variant is present in population databases (rs528069912, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Chudley-McCullough syndrome (PMID: 22578326). This variant is also known as c.741delC (p.N247NfsX34). ClinVar contains an entry for this variant (Variation ID: 35492). For these reasons, this variant has been classified as Pathogenic.

Frameshift 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: 27180139, 30487145, 33016209, 38394064, 22987632, 22578326, 23494849)