chr17-63917337-C-T

Position:

• chr17-63917337-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R209C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GH1 NM_000515.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.17

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]

LOC112268204 (HGNC:):

ACMG classification

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/exons	MANE	UniProt
GH1	NM_000515.5	c.626G>A	p.Arg209His	missense_variant	5/5	ENST00000323322.10
LOC112268204	XR_002958148.2	n.341-260C>T		intron_variant, non_coding_transcript_variant
GH1	NM_022559.4	c.581G>A	p.Arg194His	missense_variant	5/5
GH1	NM_022560.4	c.506G>A	p.Arg169His	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GH1	ENST00000323322.10	c.626G>A	p.Arg209His	missense_variant	5/5	1	NM_000515.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32

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: 3 AN: 1461742 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727174

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: 1 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

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

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 08, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2023	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

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2007	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital	Feb 01, 2024	- -
Likely pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	.;.;D;D
Eigen	Benign	0.18
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.9	.;.;M;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.55	T
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	D
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

Other links and lift over

dbSNP: rs137853223; hg19: chr17-61994697; COSMIC: COSV100033198; COSMIC: COSV100033198;