Submissions for variant NM_013296.5(GPSM2):c.1473del (p.Phe492fs)

dbSNP: rs772372530

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224236	SCV000281030	pathogenic	not provided	2016-05-06	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV004529480	SCV000347062	pathogenic	GPSM2-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	The GPSM2 c.1473delG (p.Phe492SerfsTer5) variant, also referred to as c.1471delG, results in a frameshift and is predicted to cause a premature truncation of the protein. The p.Phe492SerfsTer5 variant has been reported in three studies in which it is found in a homozygous state in a total of nine patients with GPSM2-related disorders, including in eight individuals (including two sibling pairs) with Chudley-McCullough syndrome (CMS), and in one individual with a recessive form of nonsyndromic hearing loss (Doherty et al. 2012; Schrauwen et al. 2013; Almomani et al. 2013). The p.Phe492SerfsTer5 variant was absent from a single control and is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium, though this is based on only two alleles so it is presumed to be rare. Due to the potential impact of frameshift variants and supporting evidence from the literature, this variant is classified as pathogenic for GPSM2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000607932	SCV000712254	pathogenic	Rare genetic deafness	2016-06-09	criteria provided, single submitter	clinical testing	The p.Phe492fs variant in GPSM2 has been previously reported in 6 homozygous ind ividuals with Chudley McCullough syndrome (CMS) and 1 homozygous individual with sensorineural hearing loss, and it segregated in two affected siblings (Almoman i 2013, Doherty 2012, Hendriks 1999, Schrauwen 2013). CMS is characterized by s ensorineural hearing loss, typically in the severe to profound range, with chara cteristic abnormalities on brain MRI. Despite the brain abnormalities found on i maging, individuals with CMS do not typically have cognitive or developmental ab normalities. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 492 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. In summary, this variant meets our crit eria to be classified as pathogenic for Chudley McCullough syndrome in an autoso mal recessive manner based on the predicted impact of the variant and previously reported affected individuals.
GeneDx	RCV000224236	SCV002762492	pathogenic	not provided	2022-11-30	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23208854, 22578326, 27180139, 23494849, 32445360, 28555434)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000224236	SCV004291965	pathogenic	not provided	2022-11-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 291707). This premature translational stop signal has been observed in individual(s) with hearing loss (PMID: 23208854). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Phe492Serfs*5) 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).
OMIM	RCV002282113	SCV000051808	pathogenic	Chudley-McCullough syndrome	2012-06-08	no assertion criteria provided	literature only