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

Total submissions: 6

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.