VCV001206352.6 - ClinVar

NM_000163.5(GHR):c.192_193del (p.Ser65fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000163.5(GHR):c.192_193del (p.Ser65fs)

Variation ID: 1206352 Accession: VCV001206352.6

Type and length

Deletion, 2 bp

Location

Cytogenetic: 5p12 5: 42688942-42688943 (GRCh38) [ NCBI UCSC ] 5: 42689044-42689045 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 21, 2021	Sep 16, 2024	Jul 7, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000163.5:c.192_193del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000154.1:p.Ser65fs	frameshift
NM_000163.4:c.192_193del
NM_001242399.2:c.213_214del	NP_001229328.1:p.Ser72fs	frameshift
NM_001242400.2:c.192_193del	NP_001229329.1:p.Ser65fs	frameshift
NM_001242401.4:c.192_193del	NP_001229330.1:p.Ser65fs	frameshift
NM_001242402.2:c.192_193del	NP_001229331.1:p.Ser65fs	frameshift
NM_001242403.3:c.192_193del	NP_001229332.1:p.Ser65fs	frameshift
NM_001242404.2:c.192_193del	NP_001229333.1:p.Ser65fs	frameshift
NM_001242405.2:c.192_193del	NP_001229334.1:p.Ser65fs	frameshift
NM_001242406.2:c.192_193del	NP_001229335.1:p.Ser65fs	frameshift
NM_001242460.2:c.126_127delTT	NP_001229389.1:p.Ser43Metfs	frameshift
NM_001242462.1:c.192_193del	NP_001229391.1:p.Ser65fs	frameshift
NC_000005.10:g.42688945_42688946del
NC_000005.9:g.42689047_42689048del
NG_011688.2:g.270022_270023del

... more HGVS ... less HGVS

Protein change

S43fs, S65fs, S72fs

Other names

Canonical SPDI

NC_000005.10:42688941:TTTTT:TTT

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 600946.0011 dbSNP: rs1194378231 VarSome

Comment on variant

NCBI staff provided an HGVS expression for allelic variant 600946.0011 from the sequence reported in Figure 2b of the paper by Berg et al.,1993 (PMC1682057).

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GHR		-	-	GRCh38 GRCh37	484	527

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 7, 2023	RCV001573917.5
Laron-type isolated somatotropin defect	Pathogenic (2)	criteria provided, single submitter	Dec 13, 2022	RCV002279943.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 13, 2022)	criteria provided, single submitter (Accession Criteria ClinVar Biomnis) Method: clinical testing	Laron-type isolated somatotropin defect Affected status: yes Allele origin: biparental	Eurofins-Biomnis Accession: SCV003935113.1 First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023
Pathogenic (May 22, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004293718.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 8488849‚ 1999489 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1206352). This variant is also known … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1206352). This variant is also known as 45delTT. This premature translational stop signal has been observed in individual(s) with autosomal recessive Laron syndrome (PMID: 8488849). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ser65Metfs*6) in the GHR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GHR are known to be pathogenic (PMID: 1999489, 8488849). (less)
Pathogenic (Jul 07, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005201762.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Comment: Seen with a second variant in a patient with Laron syndrome, however it is unclear if the variants are on the same or opposite chromosomes … (more) Seen with a second variant in a patient with Laron syndrome, however it is unclear if the variants are on the same or opposite chromosomes (Berg et al., 1993); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9076344, 8488849) (less)
Pathogenic (May 01, 1993)	no assertion criteria provided Method: literature only	LARON SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029390.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 8488849 Comment on evidence: In 2 unrelated Spanish patients with Laron syndrome (262500), Berg et al. (1993) found homozygosity for a deletion of TT at codon 46 in one … (more) In 2 unrelated Spanish patients with Laron syndrome (262500), Berg et al. (1993) found homozygosity for a deletion of TT at codon 46 in one and compound heterozygosity for this mutation in the second. The 2-bp deletion resulted in a nonsense mutation 5 codons downstream from codon 46. The parents were consanguineous in the first family, but were not consanguineous in the second. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800463.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001974300.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1206352). This variant is also known as 45delTT. This premature translational stop signal has been observed in individual(s) with autosomal recessive Laron syndrome (PMID: 8488849). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ser65Metfs*6) in the GHR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GHR are known to be pathogenic (PMID: 1999489, 8488849).

Comment:

Seen with a second variant in a patient with Laron syndrome, however it is unclear if the variants are on the same or opposite chromosomes (Berg et al., 1993); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9076344, 8488849)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diverse growth hormone receptor gene mutations in Laron syndrome.	Berg MA	American journal of human genetics	1993	PMID: 8488849
Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism.	Amselem S	The Journal of clinical investigation	1991	PMID: 1999489

Text-mined citations for rs1194378231 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000163.5(GHR):c.192_193del (p.Ser65fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1194378231 ...