NM_007373.4(SHOC2):c.74A>G (p.Glu25Gly) AND Noonan syndrome-like disorder with loose anagen hair 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 8, 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:: RCV001004912.3

Allele description [Variation Report for NM_007373.4(SHOC2):c.74A>G (p.Glu25Gly)]

NM_007373.4(SHOC2):c.74A>G (p.Glu25Gly)

Gene:

SHOC2:SHOC2 leucine rich repeat scaffold protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q25.2

Genomic location:

Preferred name:

NM_007373.4(SHOC2):c.74A>G (p.Glu25Gly)

Other names:

p.E25G:GAA>GGA

HGVS:

NC_000010.11:g.110964432A>G
NG_028922.1:g.49890A>G
NM_001269039.3:c.74A>G
NM_001324336.2:c.74A>G
NM_001324337.2:c.74A>G
NM_007373.4:c.74A>GMANE SELECT
NP_001255968.1:p.Glu25Gly
NP_001311265.1:p.Glu25Gly
NP_001311266.1:p.Glu25Gly
NP_031399.2:p.Glu25Gly
NP_031399.2:p.Glu25Gly
LRG_753t1:c.74A>G
LRG_753:g.49890A>G
LRG_753p1:p.Glu25Gly
NC_000010.10:g.112724190A>G
NM_007373.3:c.74A>G
p.Glu25Gly

Protein change:

E25G

Links:

dbSNP: rs730881019

NCBI 1000 Genomes Browser:

rs730881019

Molecular consequence:

NM_001269039.3:c.74A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001324336.2:c.74A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001324337.2:c.74A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_007373.4:c.74A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Noonan syndrome-like disorder with loose anagen hair 1 (NSLH1)
Synonyms:: TOSTI SYNDROME; MAZZANTI SYNDROME
Identifiers:: MONDO: MONDO:0054637; MedGen: C4478716; Orphanet: 2701; OMIM: 607721

Recent activity

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hypothetical protein BPKS7gp39 [Salmonella phage SS3e]
hypothetical protein BPKS7gp39 [Salmonella phage SS3e]
gi|62327348|ref|YP_224061.1|

Protein
Rattus norvegicus TL0ADA7YD01 mRNA sequence
Rattus norvegicus TL0ADA7YD01 mRNA sequence
gi|298906822|emb|FQ228541.1|

Nucleotide
yy74a10.s1 Soares_multiple_sclerosis_2NbHMSP Homo sapiens cDNA clone IMAGE:27925...
yy74a10.s1 Soares_multiple_sclerosis_2NbHMSP Homo sapiens cDNA clone IMAGE:279258 3', mRNA sequence
gi|1187508|gnl|dbEST|451871|gb|N463

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001164417	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 3, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV004171417	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Sep 8, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001164417

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 3, 2018)

germline

research

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

SCV004171417

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Uncertain significance
(Sep 8, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164417.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

Description

The heterozygous p.Glu25Gly variant in SHOC2 was identified by our study in one individual with Noonan syndrome-like disorder with loose anagen hair. This variant has been identified in 0.009531% (12/125906) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs730881019). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has been reported a VUS in ClinVar (Variation ID: 40637). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Glu25Gly variant is uncertain. ACMG/AMP Criteria applied: PP3 (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV004171417.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The SHOC2 c.74A>G (p.Glu25Gly) missense change has a maximum subpopulation frequency of 0.01% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Noonan syndrome-like disorder. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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