ClinVar Miner

Submissions for variant NM_024577.4(SH3TC2):c.3143T>C (p.Leu1048Pro)

gnomAD frequency: 0.00001  dbSNP: rs537759361
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000992972 SCV001145609 uncertain significance not provided 2018-12-19 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre RCV001173831 SCV001336947 uncertain significance Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001321191 SCV001512010 pathogenic Charcot-Marie-Tooth disease type 4 2024-10-29 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1048 of the SH3TC2 protein (p.Leu1048Pro). This variant is present in population databases (rs537759361, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 29336362, 31211173, 33643188; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 805447). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SH3TC2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002320205 SCV002609043 uncertain significance Inborn genetic diseases 2020-08-27 criteria provided, single submitter clinical testing The p.L1048P variant (also known as c.3143T>C), located in coding exon 13 of the SH3TC2 gene, results from a T to C substitution at nucleotide position 3143. The leucine at codon 1048 is replaced by proline, an amino acid with similar properties. This variant was detected in the homozygous state in a Chinese individual with infantile-onset Charcot-Marie-Tooth disease (CMT) (Chen CX et al. Clin. Genet., 2019 11;96:439-448), and in the heterozygous state in a Chinese individual with adolescent-onset CMT (Zhao X et al. Chin. Med. J., 2018 Jan;131:151-155). In addition, this variant was reported to be compound heterozygous with another SH3TC2 variant (p.L139del, c.415_417del) in a Chinese CMT cohort; however, clinical details were limited (Hsu YH et al. Ann Clin Transl Neurol, 2019 Jun;6:1090-1101). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000992972 SCV003800405 uncertain significance not provided 2022-06-22 criteria provided, single submitter clinical testing The SH3TC2 c.3143T>C, p.Leu1048Pro variant (rs537759361; ClinVar Variation ID: 805447) is reported in the literature in individuals affected with symptoms of Charcot-Marie-Tooth disease (Duan 2021, Hsu 2019, Volodarsky 2021, Zhao 2018). However, this variant has only been observed in trans with established pathogenic variation in a single individual (Duan 2021). This variant is found in the East Asian population with an allele frequency of 0.08% (15/18388 alleles) in the Genome Aggregation Database. The leucine at codon 1048 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.855). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Duan X et al. Characteristics of Clinical and Electrophysiological Pattern in a Large Cohort of Chinese Patients With Charcot-Marie-Tooth 4C. Front Neurol. 2021 Feb 12;12:598168. PMID: 33643188. Hsu YH et al. Mutation spectrum of Charcot-Marie-Tooth disease among the Han Chinese in Taiwan. Ann Clin Transl Neurol. 2019 May 27;6(6):1090-1101. PMID: 31211173. Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792. Zhao X et al. Screening for SH3TC2, PMP2, and BSCL2 Variants in a Cohort of Chinese Patients with Charcot-Marie-Tooth. Chin Med J (Engl). 2018 Jan 20;131(2):151-155. PMID: 29336362.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003230612 SCV003928581 uncertain significance not specified 2023-04-26 criteria provided, single submitter clinical testing Variant summary: SH3TC2 c.3143T>C (p.Leu1048Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251314 control chromosomes. c.3143T>C has been reported in the literature in individuals affected with Charcot-Marie-Tooth disease type 4C (Zhao_2018, Hsu_2019, Chen_2019, Volodarsky_2021, Duan_2021, Xie_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29336362, 31211173, 31372974, 32376792, 33643188, 34255403). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic n=1, VUS n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics RCV005036265 SCV005668520 likely pathogenic Charcot-Marie-Tooth disease type 4C; Susceptibility to mononeuropathy of the median nerve, mild 2024-03-05 criteria provided, single submitter clinical testing

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