Submissions for variant NM_024577.4(SH3TC2):c.386-2A>C

gnomAD frequency: 0.00001  dbSNP: rs145670786

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035277	SCV001198600	pathogenic	Charcot-Marie-Tooth disease type 4	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the SH3TC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SH3TC2 are known to be pathogenic (PMID: 20220177, 27068304). This variant is present in population databases (rs145670786, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with hereditary neuropathy (internal data). ClinVar contains an entry for this variant (Variation ID: 694977). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001556920	SCV001778588	pathogenic	not provided	2024-10-31	criteria provided, single submitter	clinical testing	Reported previously in a patient with demyelinating CMT with delayed walking, falls, scoliosis, facial weakness, hoarseness, and a positive family history who also harbored a deletion in SH3TC2 (phase unknown) (PMID: 31827005); Reported previously in a large cohort of patients with CMT; however, no other information was provided (PMID: 25614874); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon 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: 36947133, 31827005, 25614874)
Ambry Genetics	RCV002352497	SCV002619989	likely pathogenic	Inborn genetic diseases	2020-10-26	criteria provided, single submitter	clinical testing	The c.386-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 5 in the SH3TC2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown. This alteration has been reported in trans with other pathogenic alterations in SH3TC2 in individuals with clinical features consistent with Charcot-Marie-Tooth disease, type 4C (CMT4C) (Cortese A et al. Neurology, 2020 01;94:e51-e61). Based on data from gnomAD, the C allele has an overall frequency of 0.001% (3/251434) total alleles studied. The highest observed frequency was 0.003% (3/113740) of European (non-Finnish) alleles. This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789241	SCV005398779	pathogenic	Charcot-Marie-Tooth disease type 4C	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, type 4C (CMT) (MIM#601596). The mechanism of disease for mild mononeuropathy of the median nerve (MIM#613353) is unknown, but gain of function has been suggested (PMID: 20220177). (I) 0108 - This gene is associated with both recessive and dominant disease. CMT is caused by biallelic variants, while autosomal dominant mild mononeuropathy of the median nerve is rare and has been reported in one family (OMIM, PMID: 20220177). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. c.386-15G>A has been observed as compound heterozygous with a nonsense variant in two individuals from the same family with CMT. RNA studies show that this variant causes abnormal splicing (PMID: 30001926). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar, and observed as compound heterozygous with an exon 7 deletion in two siblings with CMT (PMID: 31827005). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005036240	SCV005670646	likely pathogenic	Charcot-Marie-Tooth disease type 4C; Susceptibility to mononeuropathy of the median nerve, mild	2024-03-07	criteria provided, single submitter	clinical testing
Genesis Genome Database	RCV000857159	SCV000999740	uncertain significance	Distal spinal muscular atrophy	2019-08-14	no assertion criteria provided	research