NM_015937.6(PIGT):c.1342C>T (p.Arg448Trp) AND Multiple congenital anomalies-hypotonia-seizures syndrome 3

Clinical significance:Likely pathogenic (Last evaluated: Dec 31, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000132728.3

Allele description [Variation Report for NM_015937.6(PIGT):c.1342C>T (p.Arg448Trp)]

NM_015937.6(PIGT):c.1342C>T (p.Arg448Trp)

Gene:
PIGT:phosphatidylinositol glycan anchor biosynthesis class T [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
20q13.12
Genomic location:
Preferred name:
NM_015937.6(PIGT):c.1342C>T (p.Arg448Trp)
Other names:
R488W
HGVS:
  • NC_000020.11:g.45424323C>T
  • NG_047154.1:g.13257C>T
  • NM_001184728.3:c.1174C>T
  • NM_001184729.3:c.1141C>T
  • NM_001184730.3:c.1036C>T
  • NM_015937.6:c.1342C>TMANE SELECT
  • NP_001171657.1:p.Arg392Trp
  • NP_001171658.1:p.Arg381Trp
  • NP_001171659.1:p.Arg346Trp
  • NP_057021.2:p.Arg448Trp
  • NC_000020.10:g.44052963C>T
  • NM_015937.4:c.1342C>T
  • NM_015937.5:c.1342C>T
  • NR_047691.2:n.1318C>T
  • NR_047692.2:n.1261C>T
  • NR_047693.2:n.1257C>T
  • NR_047694.2:n.1180C>T
  • NR_047695.2:n.951C>T
Protein change:
R346W; ARG488TRP
Links:
OMIM: 610272.0004; dbSNP: rs527236031
NCBI 1000 Genomes Browser:
rs527236031
Molecular consequence:
  • NM_001184728.3:c.1174C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001184729.3:c.1141C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001184730.3:c.1036C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_015937.6:c.1342C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_047691.2:n.1318C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_047692.2:n.1261C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_047693.2:n.1257C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_047694.2:n.1180C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_047695.2:n.951C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Multiple congenital anomalies-hypotonia-seizures syndrome 3 (MCAHS3)
Synonyms:
GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 7
Identifiers:
MONDO: MONDO:0014165; MedGen: C3809356; Orphanet: 369837; OMIM: 615398

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000187657Undiagnosed Diseases Program Translational Research Laboratory,National Institutes of Healthno assertion criteria providedpathogenicinheritednot provided

SCV000267597OMIMno assertion criteria providedPathogenic
(Apr 25, 2016)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV000957008Invitaecriteria provided, single submitter
Likely pathogenic
(Dec 31, 2018)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod

Citations

PubMed

Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors.

Lam C, Golas GA, Davids M, Huizing M, Kane MS, Krasnewich DM, Malicdan MCV, Adams DR, Markello TC, Zein WM, Gropman AL, Lodish MB, Stratakis CA, Maric I, Rosenzweig SD, Baker EH, Ferreira CR, Danylchuk NR, Kahler S, Garnica AD, Bradley Schaefer G, Boerkoel CF, et al.

Mol Genet Metab. 2015 Jun-Jul;115(2-3):128-140. doi: 10.1016/j.ymgme.2015.04.007. Epub 2015 May 1.

PubMed [citation]
PMID:
25943031
PMCID:
PMC6341466

Novel compound heterozygous PIGT mutations caused multiple congenital anomalies-hypotonia-seizures syndrome 3.

Nakashima M, Kashii H, Murakami Y, Kato M, Tsurusaki Y, Miyake N, Kubota M, Kinoshita T, Saitsu H, Matsumoto N.

Neurogenetics. 2014 Aug;15(3):193-200. doi: 10.1007/s10048-014-0408-y. Epub 2014 Jun 8.

PubMed [citation]
PMID:
24906948
See all PubMed Citations (3)

Details of each submission

From Undiagnosed Diseases Program Translational Research Laboratory,National Institutes of Health, SCV000187657.1

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

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritednot provided1not providednot providednot providednot providednot providednot provided

From OMIM, SCV000267597.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

For discussion of the c.1342C-T transition (c.1342C-T, NM_015937.5) in the PIGT gene, resulting in an arg488-to-trp (R488W) substitution, that was found in compound heterozygous state in a patient with multiple congenital anomalies-hypotonia-seizures syndrome-3 (MCAHS3; 615398) by Nakashima et al. (2014), see 610272.0003.

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

From Invitae, SCV000957008.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces arginine with tryptophan at codon 448 of the PIGT protein (p.Arg448Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs527236031, ExAC 0.01%). This variant has been observed to segregate with multiple congenital anomalies-hypotonia-seizures syndrome in a family and has been also found in an unrelated individual with the same pathology (PMID: 24906948, 25943031). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 143194). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Jul 13, 2021

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