ClinVar Miner

Submissions for variant NM_006415.4(SPTLC1):c.992C>A (p.Ser331Tyr) (rs267607087)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414705 SCV000491282 pathogenic not provided 2016-11-04 criteria provided, single submitter clinical testing The S331Y pathogenic variant in the SPTLC1 gene has been reported previously as a heterozygous de novo variant in an individual with a diagnosis of HSN1A who presented with normal early development followed by failure to thrive in childhood, abnormal gait, frequent falls, and moderate hand tremor. Later in childhood, general muscle hypotrophy and hypotonia with pronounced limb weakness, growth retardation, fasciculations, joint hypermobility, juvenile cataracts, foot burns and scars and prominent sensory disturbances were noted (Auer-Grumbach et al., 2013). The S331Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S331Y variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies show a significant reduction in the canonical SPT activity and a significant increase of 1-deoxy-sphinganin formation in HEK293 cells compared to wild type cells (Auer-Grumbach et al., 2013; Bode et al., 2016). A missense variant at the same residue (S331F) has also been reported in multiple individuals with severe and early onset HSN1A (Rotthier et al., 2011; Rotthier et al., 2009). Therefore, we interpret S331Y as a pathogenic variant.
Invitae RCV000795948 SCV000935430 pathogenic Hereditary sensory and autonomic neuropathy type 1 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces serine with tyrosine at codon 331 of the SPTLC1 protein (p.Ser331Tyr). The serine residue is highly conserved and there is a large physicochemical difference between serine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with SPTCL1-related disease (PMID: 23454272). ClinVar contains an entry for this variant (Variation ID: 372788). This variant has been reported to affect SPTLC1 protein function (PMID: 26681808). This variant disrupts the p.Ser331 amino acid residue in SPTLC1. Other variant(s) that disrupt this residue has been observed in individuals with SPTLC1-related conditions (PMID: 21618344, 19651702, 24247255), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Inherited Neuropathy Consortium RCV000790228 SCV000929620 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
OMIM RCV001249813 SCV000996521 pathogenic Neuropathy, hereditary sensory and autonomic, type IA, severe 2019-10-23 no assertion criteria provided literature only

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