ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000656975 SCV000892443 uncertain significance not provided 2018-09-30 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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656975 SCV000337895 uncertain significance not provided 2015-12-02 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.
GeneReviews RCV000002590 SCV000054694 pathologic Charcot-Marie-Tooth disease, type 4C 2012-09-13 no assertion criteria provided curation Converted during submission to Pathogenic.
Invitae RCV000199719 SCV000255069 likely benign Charcot-Marie-Tooth disease type 4 2018-01-04 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

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