ClinVar Miner

Submissions for variant NM_006415.4(SPTLC1):c.431T>A (p.Val144Asp) (rs119482083)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235837 SCV000293136 likely pathogenic not provided 2018-08-28 criteria provided, single submitter clinical testing The V144D variant in the SPTLC1 gene has been previously reported in multiple individuals with hereditary sensory neuropathy type I (Dawkins et al., 2001; Mourad et al., 2009). Two unrelated individuals with V144D were reported to have a mild phenotype including mild sensory loss, minimal ulceration and no hearing abnormalities; however the ages of these patients was not provided (Mourad et al., 2009). Functional studies show that V144D is associated with reduced SPT activity (Hornemann et al., 2009). Protein expression studies show that V144D is associated with changes to the mitochondrial proteins (Stimpson et al., 2015); additionally, V144D is associated with structural changes to the mitochondria including electron dense and enlarged cristae (Myers et al., 2014). The V144D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). V144D is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. Therefore, we interpret V144D as a likely pathogenic variant.
Invitae RCV000005068 SCV000626933 pathogenic Hereditary sensory and autonomic neuropathy type 1 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces valine with aspartic acid at codon 144 of the SPTLC1 protein (p.Val144Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid. This variant is present in population databases (rs119482083, ExAC 0.002%). This variant has been observed in individual(s) with hereditary sensory neuropathy (PMID: 11242114, Invitae). ClinVar contains an entry for this variant (Variation ID: 4801). This variant has been reported to affect SPTLC1 protein function (PMID: 11242114, 19132419, 25584079, 24673574, 26681808). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV001249799 SCV000894482 likely pathogenic Neuropathy, hereditary sensory and autonomic, type 1A 2018-10-31 criteria provided, single submitter clinical testing
Molecular Genetics Laboratory,London Health Sciences Centre RCV001174070 SCV001337190 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
OMIM RCV001249799 SCV000025244 pathogenic Neuropathy, hereditary sensory and autonomic, type 1A 2001-03-01 no assertion criteria provided literature only
GeneReviews RCV001249799 SCV000058074 pathologic Neuropathy, hereditary sensory and autonomic, type 1A 2013-03-07 no assertion criteria provided curation Converted during submission to Pathogenic.

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