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

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000656975	SCV000255069	likely benign	not provided	2019-02-28	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	2018-06-01	criteria provided, single submitter	clinical testing
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.