Submissions for variant NM_024577.3(SH3TC2):c.505T>C (p.Tyr169His) (rs80359890)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001079620	SCV000255069	likely benign	Charcot-Marie-Tooth disease type 4	2019-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000656975	SCV000292686	uncertain significance	not provided	2019-01-04	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SH3TC2 gene. The Y169H variant in the SH3TC2 gene has been reported previously in association with two neuropathy phenotypes in a single family (Lupski et al., 2010; Lupski et al., 2013). In this family, individuals with the Y169H variant and the p.M1? variant on one chromosome (in cis) and the R954X nonsense pathogenic variant on the other chromosome (in trans) exhibited a Charcot-Marie-Tooth phenotype, while individuals with only the Y169H variant and the p.M1? variant in cis exhibited a subclinical axonopathy phenotype; however, in the absence of functional data the authors were unable to conclude if Y169H is pathogenic on its own or if it is a benign variant in cis with a pathogenic variant (Lupski et al., 2013). Y169H was also reported in a patient with early-onset foot deformities who had a pathogenic variant in trans (Lassuthova et al., 2011). The patient's brother was also compound heterozygous for Y169H and the pathogenic variant; however, he refused examination and it is unknown if he was affected (Lassuthova et al., 2011). Most recently Y169H was reported in 2 siblings with infantile spinal muscular atrophy and peripheral neuropathy who also had a pathogenic deletion in the SNM1 gene; the Y169H variant was also observed in the children's healthy father (Rudnick-Schoneborn et al., 2016). The Y169H variant is observed in 394/126,688 (0.3%) alleles from individuals of European background, including 1 homozygous individual, in large population cohorts (Lek et al., 2016). The Y169H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000656975	SCV000337895	uncertain significance	not provided	2015-12-02	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000415264	SCV000492854	uncertain significance	Hemihypertrophy; Scoliosis; Congenital contracture; Arthrogryposis multiplex congenita; Decreased muscle mass; Short lower limbs; Upper limb undergrowth	2014-03-24	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000656975	SCV000892443	uncertain significance	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000002591	SCV001319181	uncertain significance	Mononeuropathy of the median nerve, mild	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001172848	SCV001335921	likely benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000002590	SCV001440840	uncertain significance	Charcot-Marie-Tooth disease, type 4C	2019-01-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001287146	SCV001473797	uncertain significance	none provided	2020-03-03	criteria provided, single submitter	clinical testing	The SH3TC2 c.505T>C; p.Tyr169His variant (rs80359890) is reported in the literature in several families affected with Charcot-Marie-Tooth (CMT) disease (Lassuthova 2011, Lupski 2013), While this variant was found in trans to a pathogenic variant in one individual (Lassuthova 2011), it was found in cis to a start-loss variant in a different family (Lupski 2013). The p.Tyr169His variant is found in the non-Finnish European population with an overall allele frequency of 0.31% (403/129164 alleles, including one homozygotes) in the Genome Aggregation Database. The tyrosine at codon 169 is highly conserved but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Lassuthova P et al. High frequency of SH3TC2 mutations in Czech HMSN I patients. Clin Genet. 2011 Oct;80(4):334-45. Lupski JR et al. Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy. Genome Med. 2013 Jun 27;5(6):57.
OMIM	RCV000002590	SCV000022748	pathogenic	Charcot-Marie-Tooth disease, type 4C	2010-04-01	no assertion criteria provided	literature only
OMIM	RCV000002591	SCV000022749	pathogenic	Mononeuropathy of the median nerve, mild	2010-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000002590	SCV000054694	pathologic	Charcot-Marie-Tooth disease, type 4C	2012-09-13	no assertion criteria provided	curation	Converted during submission to Pathogenic.