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NM_006415.4(SPTLC1):c.431T>A (p.Val144Asp) AND not provided

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Jun 22, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000235837.8

Allele description [Variation Report for NM_006415.4(SPTLC1):c.431T>A (p.Val144Asp)]

NM_006415.4(SPTLC1):c.431T>A (p.Val144Asp)

Gene:
SPTLC1:serine palmitoyltransferase long chain base subunit 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9q22.31
Genomic location:
Preferred name:
NM_006415.4(SPTLC1):c.431T>A (p.Val144Asp)
HGVS:
  • NC_000009.12:g.92068095A>T
  • NG_007950.1:g.52314T>A
  • NM_001281303.2:c.431T>A
  • NM_001368272.1:c.65T>A
  • NM_001368273.1:c.-35T>A
  • NM_006415.4:c.431T>AMANE SELECT
  • NP_001268232.1:p.Val144Asp
  • NP_001355201.1:p.Val22Asp
  • NP_006406.1:p.Val144Asp
  • LRG_272t1:c.431T>A
  • LRG_272:g.52314T>A
  • LRG_272p1:p.Val144Asp
  • NC_000009.11:g.94830377A>T
  • NM_006415.2:c.431T>A
  • NM_006415.3:c.431T>A
  • O15269:p.Val144Asp
Protein change:
V144D; VAL144ASP
Links:
UniProtKB: O15269#VAR_011394; OMIM: 605712.0003; dbSNP: rs119482083
NCBI 1000 Genomes Browser:
rs119482083
Molecular consequence:
  • NM_001368273.1:c.-35T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001281303.2:c.431T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001368272.1:c.65T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_006415.4:c.431T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000293136GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Likely pathogenic
(Oct 18, 2022) 		germlineclinical testing

Citation Link,

SCV004229214Athena Diagnostics
criteria provided, single submitter

(Athena Diagnostics Criteria)		Pathogenic
(Jun 22, 2023) 		unknownclinical testing

PubMed (12)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.

Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer-Grumbach M, Nicholson GA.

Nat Genet. 2001 Mar;27(3):309-12.

PubMed [citation]
PMID:
11242114

A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.

Hornemann T, Penno A, Richard S, Nicholson G, van Dijk FS, Rotthier A, Timmerman V, von Eckardstein A.

Neurogenetics. 2009 Apr;10(2):135-43. doi: 10.1007/s10048-008-0168-7. Epub 2009 Jan 9.

PubMed [citation]
PMID:
19132419
See all PubMed Citations (12)

Details of each submission

From GeneDx, SCV000293136.13

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Reported in multiple individuals with hereditary neuropathy previously tested at at GeneDx and in the published literature (Dawkins et al., 2001; Vogt et al., 2020); Protein expression studies show that p.(V144D) is associated with changes to the mitochondrial proteins (Stimpson et al., 2015); additionally, p.(V144D) is associated with structural changes to the mitochondria including electron dense and enlarged cristae (Myers et al., 2014).; Published functional studies demonstrate a damaging effect on SPT activity and calcium regulation (Antony et al., 2022; Hornemann et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30420926, 26681808, 25584079, 33497257, 34986032, 30778062, 34337561, 32730653, 15546589, 26395456, 24175284, 23454272, 30762923, 20920666, 24673574, 19132419, 32195206, 32399692, 20301564, 18348718, 25947379, 35895683, 35181405, 35904184, 35899376, 11242114)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Athena Diagnostics, SCV004229214.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals, and segregates with disease in at least one family with HSAN. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11781309, 19132419)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2024