rs111033259

Positions:

• chr11-77198596-GAGATCATG-GCA

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1 PM2 PM4 PP3 PP5_Very_Strong

The NM_000260.4(MYO7A):​c.4544_4551delAGATCATGinsCA​(p.Glu1515_Met1517delinsAla) variant causes a missense, conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO7A NM_000260.4 missense, conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.67

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

MYO7A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PS1: Transcript NM_000260.4 (MYO7A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000260.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 11-77198597-AGATCATG-CA is Pathogenic according to our data. Variant chr11-77198597-AGATCATG-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.4544_4551delAGATCATGinsCA	p.Glu1515_Met1517delinsAla	missense_variant, conservative_inframe_deletion		ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4544_4551delAGATCATGinsCA	p.Glu1515_Met1517delinsAla	missense_variant, conservative_inframe_deletion		1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4544_4551delAGATCATGinsCA	p.Glu1515_Met1517delinsAla	missense_variant, conservative_inframe_deletion		1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4511_4518delAGATCATGinsCA	p.Glu1504_Met1506delinsAla	missense_variant, conservative_inframe_deletion		1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.2087_2094delAGATCATGinsCA	p.Glu696_Met698delinsAla	missense_variant, conservative_inframe_deletion		1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2384_2391delAGATCATGinsCA		non_coding_transcript_exon_variant	17/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 25, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 08, 2022	This variant, c.4544_4551delinsCA, is a complex sequence change that results in the deletion of 3 and insertion of 1 amino acid(s) in the MYO7A protein (p.Glu1515_Met1517delinsAla). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with clinical features of Usher syndrome (PMID: 16963483, 27743452; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.4543_4551delGAGATCATGinsGCA. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2023	In-frame deletion of 3 amino acids and an insertion of 1 amino acid in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16963483, 33576163, 27743452) -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 07, 2011

The Glu1515_Met1517delinsAla variant in MYO7A has been identified in three proba nds with Usher syndrome (personal communication, W. Kimberling and two in our la boratory). The variant replaces three amino acids with a single new amino acid a nd is therefore likely to impact protein function. In addition, two probands hav e a second pathogenic variant in MYO7A which further supports a causative role. And finally, one proband?s affected sibling was also found to harbor both the 64 39-2A>G variant and this MYO7A variant and parental testing showed the variants were in trans (on two separate copies of the gene). In summary, this data suppor ts the classification of this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033259; hg19: chr11-76909642;