17-63917337-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000515.5(GH1):c.626G>A(p.Arg209His) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GH1
NM_000515.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.17

Variant links:

Genes affected

GH1 (HGNC:4261): (growth hormone 1) The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. The five genes share a remarkably high degree of sequence identity. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed in the pituitary but not in placental tissue as is the case for the other four genes in the growth hormone locus. Mutations in or deletions of the gene lead to growth hormone deficiency and short stature. [provided by RefSeq, Jul 2008]

GH1 links:

ENSG00000285947 (HGNC:):

ENSG00000285947 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 17-63917337-C-T is Pathogenic according to our data. Variant chr17-63917337-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GH1	NM_000515.5 link	c.626G>A	p.Arg209His	missense_variant	Exon 5 of 5	ENST00000323322.10	NP_000506.2	P01241-1B1A4G6
GH1	NM_022559.4 link	c.581G>A	p.Arg194His	missense_variant	Exon 5 of 5		NP_072053.1	P01241-2B1A4G7
GH1	NM_022560.4 link	c.506G>A	p.Arg169His	missense_variant	Exon 4 of 4		NP_072054.1	P01241-5
LOC112268204	XR_002958148.2 link	n.341-260C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GH1	ENST00000323322.10 link	c.626G>A	p.Arg209His	missense_variant	Exon 5 of 5	1	NM_000515.5	ENSP00000312673.5		P01241-1
ENSG00000285947	ENST00000647774.1 link	c.902G>A	p.Arg301His	missense_variant	Exon 8 of 8			ENSP00000497443.1		A0A3B3ISS9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Oct 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that this variant severely impairs growth hormone secretion (Deladoey et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.6664 G>A p.R183H; This variant is associated with the following publications: (PMID: 9152628, 34006472, 33729509, 34589056, 17785368, 29739035, 11502836, 31835104) -

Jul 08, 2019

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one symptomatic patient. Conflicting predictions of the effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease in affected individuals from multiple families. -

Feb 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 209 of the GH1 protein (p.Arg209His). This variant is present in population databases (rs137853223, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal dominant growth hormone deficiency (PMID: 17785368, 29739035, 33729509, 34006472, 34589056). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg183His. ClinVar contains an entry for this variant (Variation ID: 15983). 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: "Benign"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. -

Autosomal dominant isolated somatotropin deficiency

Pathogenic:3

May 31, 2019

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Nov 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 01, 2024

Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

.;.;D;D

Eigen

Benign

0.18

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.9

.;.;M;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.3

D;D;D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.017

D;D;D;D

Sift4G

Uncertain

0.053

T;T;T;T

Polyphen

0.41, 0.87

.;.;B;P

Vest4

0.93

MutPred

0.96

.;.;Gain of glycosylation at S214 (P = 0.0589);.;

MVP

0.96

MPC

0.14

ClinPred

0.90

GERP RS

2.6

Varity_R

0.40

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over