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NM_000314.8(PTEN):c.388C>T (p.Arg130Ter) AND Macrocephaly-autism syndrome

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Jan 25, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000008265.18

Allele description [Variation Report for NM_000314.8(PTEN):c.388C>T (p.Arg130Ter)]

NM_000314.8(PTEN):c.388C>T (p.Arg130Ter)

Gene:
PTEN:phosphatase and tensin homolog [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
10q23.31
Genomic location:
Preferred name:
NM_000314.8(PTEN):c.388C>T (p.Arg130Ter)
Other names:
p.R130X:CGA>TGA; NM_000314.8(PTEN):c.388C>T; p.Arg130Ter
HGVS:
  • NC_000010.11:g.87933147C>T
  • NG_007466.2:g.74709C>T
  • NM_000314.8:c.388C>TMANE SELECT
  • NM_001304717.5:c.907C>T
  • NM_001304718.2:c.-363C>T
  • NP_000305.3:p.Arg130Ter
  • NP_000305.3:p.Arg130Ter
  • NP_001291646.4:p.Arg303Ter
  • LRG_311t1:c.388C>T
  • LRG_311:g.74709C>T
  • NC_000010.10:g.89692904C>T
  • NM_000314.4:c.388C>T
  • NM_000314.5:c.388C>T
  • NM_000314.6:c.388C>T
  • NM_000314.7:c.388C>T
  • NM_001304717.5:c.907C>T
  • NP_000305.3:p.Arg130*
  • p.Arg130X
  • p.R130*
Protein change:
R130*; ARG130TER
Links:
OMIM: 601728.0007; dbSNP: rs121909224
NCBI 1000 Genomes Browser:
rs121909224
Molecular consequence:
  • NM_001304718.2:c.-363C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000314.8:c.388C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001304717.5:c.907C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Macrocephaly-autism syndrome
Synonyms:
Macrocephaly/autism syndrome
Identifiers:
MONDO: MONDO:0011537; MedGen: C1854416; Orphanet: 210548; OMIM: 605309

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000028472OMIM
no assertion criteria provided
Pathogenic
(Mar 15, 2007) 		germlineliterature only

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

SCV002073923Center for Molecular Medicine, Children’s Hospital of Fudan University
no assertion criteria provided
Pathogenic
(Feb 8, 2022) 		de novoclinical testing

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

SCV003761297Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jan 25, 2023) 		germlinecuration

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Germline PTEN mutation in a family with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome.

Zori RT, Marsh DJ, Graham GE, Marliss EB, Eng C.

Am J Med Genet. 1998 Dec 4;80(4):399-402.

PubMed [citation]
PMID:
9856571

Increasing knowledge of PTEN germline mutations: Two additional patients with autism and macrocephaly.

Herman GE, Butter E, Enrile B, Pastore M, Prior TW, Sommer A.

Am J Med Genet A. 2007 Mar 15;143A(6):589-93.

PubMed [citation]
PMID:
17286265
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000028472.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (3)

Description

Cowden Syndrome 1

In a study of Cowden disease (CWS1; 158350), Nelen et al. (1997) found 2 independent occurrences of an arg130-to-ter (R130X) mutation in the PTEN gene. The mutation involved a CpG dinucleotide.

Zori et al. (1998) described a family in which a mother had Cowden disease and her son had been diagnosed with Bannayan-Riley-Ruvalcaba syndrome. Both were heterozygous for the R130X mutation. The son had been seen at the age of 11 years for severe developmental delay and autistic behavior. In early childhood, rectal bleeding led to removal of a few rectal polyps; the pathology showed benign pseudopolyp with telangiectatic vessels in an inflamed myxoid stroma. His verbal and performance IQs were 40 at 11 years. He developed a goiter at 18 years for which left hemithyroidectomy was performed, and a tumor was also excised from the right side of the thyroid. The left lobe contained insular (follicular) carcinoma while the right showed nodular hyperplasia with a focus of papillary microcarcinoma. At the age of 11 years, the son had multiple pigmented macules on the glands and shaft of the penis. He lacked the second toes. The mother of the patient reported by Zori et al. (1998) had a large head (59.5 cm) and multiple small papules on her tongue and oral mucosa. She had polyposis of the entire gastrointestinal tract. Mammogram showed bilateral fibroglandular tissue with single well-defined benign nodules in each breast with mild dysplasia.

Macrocephaly/Autism Syndrome

In a 4-year-old boy with macrocephaly/autism syndrome (605309), Herman et al. (2007) identified a heterozygous R130X substitution. The substitution occurs in exon 5 of the PTEN gene within the core phosphatase domain of the protein. The child inherited the mutation from his unaffected father. Herman et al. (2007) noted that the boy may develop further clinical manifestations of other PTEN-associated syndromes and emphasized that the family was counseled on the possibility of increased tumor risk in the boy and the mutation-carrying father.

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

From Center for Molecular Medicine, Children’s Hospital of Fudan University, SCV002073923.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot providednot providednot providednot providednot provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003761297.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The heterozygous p.Arg130Ter variant in PTEN was identified by our study in one individual with macrocephaly-autism syndrome (PMID: 32959437). Trio exome analysis showed this variant to be de novo. The p.Arg130Ter variant in PTEN has been previously reported in over 30 unrelated individuals with PTEN-associated disease (PMID: 29594054, PMID: 33083010, PMID: 24345843, PMID: 28655553, PMID: 28526761, PMID: 10400993, PMID: 14566704, PMID: 16773562, PMID: 11332402, PMID: 17286265, PMID: 20600018, PMID: 21194675, PMID: 23470840, PMID: 30659124, PMID: 23764071, PMID: 1191871, PMID: 10848731, PMID: 9467011, PMID: 9856571, PMID: 9259288, PMID: 21956414, SCV002059850.1) and segregated with disease in 17 affected relatives from 6 families (PMID: 28655553, PMID: 17286265, PMID: 30659124, PMID: 11332402, PMID: 9259288, PMID: 9856571), but has been identified in 0.003% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121909224). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Pathogenic variants may be present at a low frequency in the general population, for diseases with clinical variability, or reduced penetrance. The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 5 individuals with confirmed paternity and maternity (PMID: 28526761, PMID: 11918710, PMID: 32959437, PMID: 28526761, SCV002059850.1). This variant has also been reported in ClinVar (Variation ID: 7819) and has been interpreted as pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 130, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PTEN gene is an established disease mechanism in autosomal dominant PTEN-associated disease, including autosomal dominant macrocephaly-autism syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant macrocephaly-autism syndrome. ACMG/AMP Criteria applied: PVS1, PS2_VeryStrong, PS4, PP1_Strong (Richards 2015).

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

Last Updated: May 12, 2024