ClinVar Miner

Submissions for variant NM_013296.5(GPSM2):c.742del (p.Gly249fs) (rs528069912)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000223985 SCV000280912 pathogenic not provided 2016-05-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000844707 SCV000712262 pathogenic Rare genetic deafness 2016-06-09 criteria provided, single submitter clinical testing 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000223985 SCV000861996 pathogenic not provided 2018-06-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778933 SCV000915348 likely pathogenic GPSM2-Related Disorders 2018-09-24 criteria provided, single submitter clinical testing 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.
GeneDx RCV000223985 SCV001168590 pathogenic not provided 2018-11-12 criteria provided, single submitter clinical testing The c.742delC pathogenic variant in the GPSM2 gene has been reported previously in association with Chudley-McCullough syndrome (Doherty et al., 2012; Diaz-Horta et al., 2012; Almomani et al., 2013). The deletion causes a frameshift starting with codon Glycine 249, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 32 of the new reading frame, denoted Gly249GlufsX32. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant is observed in 24/126390 (0.019%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be pathogenic.
OMIM RCV000029164 SCV000051809 pathogenic Chudley-McCullough syndrome 2012-06-08 no assertion criteria provided literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000223985 SCV001808624 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000223985 SCV001966412 pathogenic not provided no assertion criteria provided clinical testing

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